Uracil derivatives as axl and c-met kinase inhibitors

ABSTRACT

The present application provides compounds of Formula I 
     
       
         
         
             
             
         
       
     
     or salt forms thereof, wherein R a , R b , R c , R d , D, W, R 1a , R 1b , R 1c , Y, R 3 , X, E and G are as defined herein, compositions, methods of treatment and uses thereof.

BACKGROUND

The present invention relates to novel compounds that are inhibitors ofthe receptor tyrosine kinases AXL and c-MET. The compounds are suitablefor treatment of AXL or c-MET-mediated disorders such as cancer, and thedevelopment of resistance to cancer therapies.

Receptor tyrosine kinases (RTKs) are transmembrane proteins thattransduce signals from the extracellular environment to the cytoplasmand nucleus to regulate normal cellular processes, including survival,growth, differentiation, adhesion, and mobility. Abnormal expression oractivation of RTKs has been implicated in the pathogenesis of varioushuman cancers, linked with cell transformation, tumor formation andmetastasis. These observations have led to intense interest in thedevelopment of tyrosine kinase inhibitors as cancer therapeutics (Rostiet al, Crit. Rev. Oncol. Hematol. 2011. [Epub ahead of print]; Gorden etal, J. Oncol. Pharm. Pract. 2011. [Epub ahead of print]; Grande et al,Mol. Cancer Ther. 2011, 10, 569).

AXL is a member of the TAM (TYRO3, AXL, MER) receptor tyrosine kinase(RTK) family originally identified as a transforming gene expressed incells from patients with chronic myelogenous leukemia (O'Bryan et. alMol. Cell Biol. 1991, 11, 5016) or chronic myeloproliferative disorder(Janssen et. al Oncogene, 1991, 6, 2113). AXL activation occurs bybinding of its cognate protein ligand, growth arrest specific 6 (Gas6),homotypic dimerization through its extracellular domain or cross-talkvia the interleukin (IL)-15 receptor or HER2. AXL signaling stimulatescellular responses, including activation of phosphoinositide3-kinase-Akt, extracellular signal-regulated kinase (ERK) and p38mitogen-activated protein kinase cascades, the NF-κB pathway, and signaltransducer and activator of transcription (STAT) signaling (Hafizi et.al Cytokine Growth Factor Rev., 2006, 17, 295). Numerous biologicalconsequences of AXL signaling, including invasion, migration, survivalsignaling, angiogenesis, resistance to chemotherapeutic and targeteddrugs, cell transformation, and proliferation, represent undesirabletraits associated with cancer (Linger et al. Adv. Cancer Res., 2008,100, 35; Hafizi et. al Cytokine Growth Factor Rev., 2006, 17, 295;Holland et al, Cancer Res. 2005, 65, 9294).

AXL receptors regulate vascular smooth muscle homeostasis (Korshunov etal, Circ. Res. 2006, 98, 1446) and are implicated in the control ofoligodendrocyte cell survival (Shankar et al, J. Neurosci. 2003, 23,4208). Studies in knockout mice have revealed that TAM receptors playpivotal roles in innate immunity by inhibiting inflammation inmacrophages and dendritic cells (Sharif et al, J. Exp. Med. 2006, 203,1891; Rothlin et al, Cell. 2007, 131, 1124), promoting the phagocytosisof apoptotic cells (Lu et al, Nature. 1999, 398, 723; Lu & Lemke,Science. 2001, 293, 306; Prasad et al, Mol. Cell Neurosci. 2006, 3, 96)and stimulating the differentiation of natural killer cells (Park et al,Blood 2009, 113, 2470).

AXL has been found to be constitutively activated due to geneamplification and/or altered protein expression (O'Bryan et al, J. Biol.Chem. 1995, 270, 551; Linger et al, Expert Opin. Ther. Targets. 2010,14, 1073; Mudduluru et al, Oncogene, 2011, 30, 2888). Altered expressionof AXL has been reported in a variety of human cancers (Crosier et al,Leuk. Lymphoma. 1995, 18, 443; Challier et al, Leukemia, 1996, 10, 781;Ito et al, Thyroid. 1999, 9, 563; Sun et al, Oncology. 2004, 66, 450;Green et al, Br. J. Cancer. 2006, 94, 1446; Liu et al, Blood. 2010, 116,297) and is associated with invasiveness and metastasis in lung cancer(Shieh et al, Neoplasia. 2005, 7, 1058), prostate cancer (Shiozawa etal, Neoplasia. 2010, 12, 116), breast cancer (Zhang et al, Cancer Res.2008, 68, 1905), esophageal cancer (Hector et al, Cancer Biol. Ther.2010, 10, 1009), ovarian cancer (Rankin et al, Cancer Res. 2010, 70,7570), pancreatic cancer (Koorstra et al, Cancer Biol. Ther. 2009, 8,618; Song et al, Cancer, 2011, 117, 734), liver cancer (He et al, Mol.Carcinog. 2010, 49, 882), gastric cancer (Wu et al, Anticancer Res.2002, 22, 1071; Sawabu et al, Mol Carcinog. 2007, 46, 155), thyroidcancer (Avilla et al, Cancer Res. 2011, 71, 1792), renal cell carcinoma(Chung et al, DNA Cell Biol. 2003, 22, 533; Gustafsson et al, Clin.Cancer Res. 2009, 15, 4742) and glioblastoma (Hutterer et al, Clin.Cancer Res. 2008, 14, 130).

Indeed, AXL overexpression is associated with late stage and pooroverall survival in many of those human cancers (Rochlitz et al,Leukemia, 1999, 13, 1352; Vajkoczy et al, Proc Natl. Acad. Sci. 2006,103, 5799). AXL contributes to at least three of the six fundamentalmechanisms of malignancy in human, by promoting cancer cell migrationand invasion, involving in tumor angiogenesis, and facilitating cancercell survival and tumor growth (Holland et al, Cancer Res. 2005, 65,9294; Tai et al, Oncogene. 2008, 27, 4044; Li et al, Oncogene, 2009, 28,3442; Mudduluru et al, Mol. Cancer Res. 2010, 8, 159). AXL is stronglyinduced by epithelial-to-mesenchymal transitions (EMT) in immortalizedmammary epithelial cells and AXL knockdown completely prevented thespread of highly metastatic breast carcinoma cells from the mammarygland to lymph nodes and several major organs and increases overallsurvival (Gjerdrum et al, Proc. Natl. Acad. Sci. USA. 2010, 107, 1124;Vuoriluoto et al, Oncogene. 2011, 30, 1436), indicating AXL represents acritical downstream effector of tumor cell EMT requiring for cancermetastasis.

AXL is also induced during progression of resistance to therapiesincluding imatinib in gastrointestinal stromal tumors (Mahadevan et al,Oncogene. 2007, 26, 3909) and Herceptin and EGFR inhibitor therapy (e.g.lapatinib) in breast cancer (Liu et al, Cancer Res. 2009, 69, 6871) viaa “tyrosine kinase switch”, and after chemotherapy in acute myeloidleukemia (Hong et al, Cancer Lett. 2008, 268, 314). AXL knockdown wasalso reported to lead to a significant increase in chemosensitivity ofastrocytoma cells in response to chemotherapy treatment (Keating et al,Mol. Cancer Ther. 2010, 9, 1298). These data indicate AXL as animportant mediator for tumor resistance to conventional chemotherapy andmolecular-based cancer therapeutics.

The c-MET receptor was initially identified as the TPR-MET oncogene inan osteosarcoma cell line treated with a chemical carcinogen. TheTPR-Met protein is able to transform and confer invasive and metastaticproperties to non-tumorigenic cells (Sattler et. al, Current OncologyRep., 2007, 9, 102). The oncogenic potential is a result of spontaneousdimerization and constitutive activation of TPR-MET. Aberrant expressionof HGF and c-MET is associated with the development and poor prognosisof a wide range of solid tumors, including breast, prostate, thyroid,lung, stomach, colorectal, pancreatic, kidney, ovarian, and uterinecarcinoma, malignant glioma, uveal melanoma, and osteo- and soft-tissuesarcoma (Jaing et. al Critical Rev. Oncol/Hematol., 2005, 53, 35).Gastric tumors with an amplification of the wt-c-MET gene are moresusceptible to MET inhibition, thereby making c-MET an attractive target(Smolen et. al Proc. Natl. Acad. Sci. USA, 2006, 103, 2316).

In vitro and in vivo studies have shown that increased and dysregulatedc-MET activation leads to a wide range of biological responsesassociated with the malignant phenotype. These responses includeincreased motility/invasion, increased tumorigenicity, enhancedangiogenesis, protection of carcinoma cells from apoptosis induced byDNA-damaging agents such as adriamycin, ultraviolet light, and ionizingradiation, and enhanced rate of repair of DNA strand breaks [Comoglioet. al J. Clin. Invest., 2002, 109, 857, Sattler et. al Current OncologyRep., 2007, 9, 102; Fan et. al, Mol. Cell Biol., 2001, 21, 4968). Basedupon these data, HGF may enhance mutagenicity following DNA damage,allowing tumor cells with genetic damage to survive, and thus leading toresistance to chemo- and radiotherapeutic treatment regimens (Fan et.al, Mol. Cell Biol., 2001, 21, 4968; Hiscox et. al Endocrine-RelatedCancer, 2004, 13, 1085).

MET amplification plays a unique critical role in mediating resistanceof non-small cell lung cancer to EGFR inhibitors (e.g. Tarceva™,Iressa™, Tykerb™) the resistance of HER2 positive breast cancer totrastuzumab (Sattler et. al, Update Cancer Ther., 2009, 3, 109; Englemanet. al, Science, 2007, 316, 1039, Shattuck et. al Cancer Res., 2008, 68,1471, Agarwal et. al, Br. J. Cancer, 2009, 100, 941; Kubo et. al, Int.J. Cancer 2009, 124, 1778). Inhibition of c-MET in Tarceva™ or Iressa™resistant cells using shRNA or small molecules alone or in combinationwith an EGFR inhibitor overcame MET-mediated resistance to EGFRinhibitors [Agarwal et. al, Br. J. Cancer, 2009, 100, 941;Bachleitner-Hoffman et. al, Mol. Cancer Ther., 2008, 7, 3499, Tang et.al, Br. J. Cancer, 2008, 99, 911; Bean et. al, Proc. Natl. Acad. Sci.USA, 2007, 104, 20932). Due to the pleiotropic, pro-tumorigenicactivities of the HGF-c-MET axis, inhibiting this pathway would bepredicted to have potent anti-tumor effects in many common cancersthrough multiple complimentary mechanisms.

A need exists for AXL and c-MET inhibitors for use as pharmaceuticalagents.

SUMMARY

The present invention provides a compound of Formula I

or a pharmaceutically acceptable salt form thereof, wherein R_(a),R_(b), R_(c), R_(d), D, W, Y, R_(1a), R_(1b), R_(1c), R₃, X, G and E areas defined herein.

The compound of Formula I has AXL and c-MET inhibitory activity, and maybe used to treat AXL-, or c-MET-mediated disorders or conditions.

The present invention further provides a pharmaceutical compositioncomprising at least one compound of the present invention together withat least one pharmaceutically acceptable carrier, diluent, or excipienttherefor.

In another aspect, the present invention provides a method of treating asubject suffering from an AXL- or c-MET-mediated disorder or conditioncomprising administering to the subject a therapeutically effectiveamount the pharmaceutical composition of the present invention.

The present invention further provides a method of treating aproliferative disorder in a subject, comprising administering to thesubject a therapeutically effective amount of a compound of the presentinvention.

DETAILED DESCRIPTION I. Definitions

As used herein, the following terms have the meanings ascribed to themunless specified otherwise.

“Alkylamino” or an “alkylamino group” refers to an —NH-alkyl group.

“Alkoxy” or “alkoxy group” refers to an —O-alkyl group.

“Alkoxycarbonyl” refers to an alkyl-O—C(═O)— group.

“Alkyl” or “alkyl group” refers to a branched or unbranched saturatedhydrocarbon chain. Examples include, but are not limited to, methyl,ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl,n-decyl, isopropyl, tert-butyl, isobutyl, etc. Alkyl groups typicallycontain 1-10 carbon atoms, such as 1-6 carbon atoms.

“Substituted alkyl” indicates that one or more hydrogen atoms on analkyl group has been replaced with a different atom or group of atomsand the atom or group of atoms replacing the hydrogen atom is a“substituent”. Representative substituents include, but are not limitedto, halogen, (C₁-C₈)alkyl, (C₁-C₈)alkoxy, (C₁-C₈)alkoxy(C₁-C₄)alkyl,carboxyl, formyl, (C₁-C₆)acyl, halo(C₁-C₄)alkyl, halo(C₁-C₄)alkoxy,hydroxyl, nitro, cyano, amino, trifluoromethyl, mono- ordi-(C₁-C₆)alkylamino, oxo, (C₆-C₁₀)aryl, (C₅-C₉)heteroaryl,(C₁-C₆)alkoxycarbonyl, (C₃-C₁₀)cycloalkyl, (C₃-C₁₀)cycloalkyloxy,(C₃-C₁₀)cycloalkyl(C₁-C₆)alkoxy, (C₂-C₉)heterocyclyl,(C₂-C₉)heterocyclyloxy, (C₂-C₉)heterocyclyl(C₁-C₄)alkoxy,(C₁-C₆)alkoxycarbonyl(C₁-C₄)alkyl, (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkylsulfinyl, (C₁-C₆)alkylsulfonyl, mono- anddi-(C₁-C₆)alkylaminocarbonyl, (C₁-C₆)acylthio, and (C₁-C₆)acyloxy.

“Alkenyl” refers to an alkyl group containing the requisite number ofcarbon atoms as described herein for “alkyl”, and which contains atleast one double bond. Representative examples of alkenyl groupsinclude, but are not limited to ethenyl, allyl, isopropenyl, and2-methyl-1-propenyl.

“Substituted alkenyl” indicates that one or more hydrogen atoms on analkenyl group has been replaced with a different atom or group of atomsand the and the atom or group of atoms replacing the hydrogen atom is a“substituent”. Representative substituents include, but are not limitedto, halogen, (C₁-C₈)alkyl, (C₁-C₈)alkoxy, (C₁-C₈)alkoxy(C₁-C₄)alkyl,carboxyl, formyl, (C₁-C₆)acyl, halo(C₁-C₄)alkyl, halo(C₁-C₄)alkoxy,hydroxyl, nitro, cyano, amino, trifluoromethyl, mono- ordi-(C₁-C₆)alkylamino, oxo, (C₆-C₁₀)aryl, (C₅-C₉)heteroaryl,(C₁-C₆)alkoxycarbonyl, (C₃-C₁₀)cycloalkyl, (C₃-C₁₀)cycloalkyloxy,(C₃-C₁₀)cycloalkyl(C₁-C₆)alkoxy, (C₂-C₉)heterocyclyl,(C₂-C₉)heterocyclyloxy, (C₂-C₉)heterocyclyl(C₁-C₄)alkoxy,(C₁-C₆)alkoxycarbonyl(C₁-C₄)alkyl, (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkylsulfinyl, (C₁-C₆)alkylsulfonyl, mono- anddi-(C₁-C₆)alkylaminocarbonyl, (C₁-C₆)acylthio, and (C₁-C₆)acyloxy.

“Alkynyl” refers to an alkyl group containing the requisite number ofcarbon atoms as described herein for “alkyl”, and which contains atleast one triple bond. Representative examples of alkenyl groupsinclude, but are not limited to ethynyl, propargyl, and 1- and2-butynyl.

“Substituted alkynyl” indicates that one or more hydrogen atoms on analkynyl group has been replaced with a different atom or group of atomsand the and the atom or group of atoms replacing the hydrogen atom is a“substituent”. Representative substituents include, but are not limitedto, halogen, (C₁-C₈)alkyl, (C₁-C₈)alkoxy, (C₁-C₈)alkoxy(C₁-C₄)alkyl,carboxyl, formyl, (C₁-C₆)acyl, halo(C₁-C₄)alkyl, halo(C₁-C₄)alkoxy,hydroxyl, nitro, cyano, amino, trifluoromethyl, mono- ordi-(C₁-C₆)alkylamino, oxo, (C₆-C₁₀)aryl, (C₅-C₉)heteroaryl,(C₁-C₆)alkoxycarbonyl, (C₃-C₁₀)cycloalkyl, (C₃-C₁₀)cycloalkyloxy,(C₃-C₁₀)cycloalkyl(C₁-C₆)alkoxy, (C₂-C₉)heterocyclyl,(C₂-C₉)heterocyclyloxy, (C₂-C₉)heterocyclyl(C₁-C₄)alkoxy,(C₁-C₆)alkoxycarbonyl(C₁-C₄)alkyl, (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkylsulfinyl, (C₁-C₆)alkylsulfonyl, mono- anddi-(C₁-C₆)alkylaminocarbonyl, (C₁-C₆)acylthio, and (C₁-C₆)acyloxy.

“Alkanoyl” refers to an alkyl-C(═O)— group.

The term “C_(x-y)” indicates the number of carbon atoms in a group. Forexample, a “C₁₋₆-alkyl” is an alkyl group having from one (1) to six (6)carbon atoms.

The term “cyano” refers to a CN group.

“Cycloalkyl” refers to a non-aromatic, saturated carbocyclic ringsystem, and may be monocyclic, bicyclic or tricyclic, and may bebridged, spiro and/or fused. Preferably the cycloalkyl group containsfrom 3 to 10 ring atoms. Examples include, but are not limited tocyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, andnorbornyl.

“Cycloalkoxyalkyl” refers to a cycloalkyl-O-alkyl- group.

“Cycloalkylalkyl” refers to a cycloalkyl-alkyl- group.

“Carbamoyl” refers to a NH₂C(═O)— group.

“N-alkylcarbamoyl” or “alkyl carbamoyl” refers to an alkyl-NH—C(═O)—group.

“N,N-dialkylcarbamoyl” or “dialkylcarbamoyl” refers to an(alkyl)(alkyl)N—C(═O)— group. On such a group the alkyl groups may bethe same or different.

“Aryl” or “aryl group” refers to phenyl and 7-15 membered monoradicalbicyclic or tricyclic hydrocarbon ring systems, including bridged,spiro, and/or fused ring systems, in which at least one of the rings isaromatic. Aryl groups can be substituted or unsubstituted. Examplesinclude, but are not limited to, phenyl, naphthyl, indanyl,1,2,3,4-tetrahydronaphthalenyl,6,7,8,9-tetrahydro-5H-benzocycloheptenyl, and6,7,8,9-tetrahydro-5H-benzocycloheptenyl. Preferably, the aryl groupcontains 6 (i.e., phenyl) or 9 to 15 ring atoms. More preferably, thearyl group contains 6 (i.e., phenyl), 9 or 10 ring atoms.

“Substituted aryl indicates that one or more hydrogen atoms on an arylgroup has been replaced with a different atom or group of atoms and theand the atom or group of atoms replacing the hydrogen atom is a“substituent”. Representative substituents include, but are not limitedto, halogen, (C₁-C₈)alkyl, (C₁-C₈)alkoxy, (C₁-C₈)alkoxy(C₁-C₄)alkyl,carboxyl, formyl, (C₁-C₆)acyl, halo(C₁-C₄)alkyl, halo(C₁-C₄)alkoxy,hydroxyl, nitro, cyano, amino, trifluoromethyl, mono- ordi-(C₁-C₆)alkylamino, oxo, (C₆-C₁₀)aryl, (C₅-C₉)heteroaryl,(C₁-C₆)alkoxycarbonyl, (C₃-C₁₀)cycloalkyl, (C₃-C₁₀)cycloalkyloxy,(C₃-C₁₀)cycloalkyl(C₁-C₆)alkoxy, (C₂-C₉)heterocyclyl,(C₂-C₉)heterocyclyloxy, (C₂-C₉)heterocyclyl(C₁-C₄)alkoxy,(C₁-C₆)alkoxycarbonyl(C₁-C₄)alkyl, (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkylsulfinyl, (C₁-C₆)alkylsulfonyl, mono- anddi-(C₁-C₆)alkylaminocarbonyl, (C₁-C₆)acylthio, and (C₁-C₆)acyloxy.

“Arylalkyl” refers to an aryl-alkyl- group.

“Arylalkoxy” refers to an aryl-alkyl-O— group.

“Arylalkoxyalkyl” refers to an aryl-alkyl-O-alkyl- group.

“Aryloxy” refers to an aryl-O— group.

“Heterocyclyl” or “heterocyclyl group” refers to 3-15 memberedmonocyclic, bicyclic, and tricyclic non-aromatic rings, which may besaturated or unsaturated, can be substituted or unsubstituted, may bebridged, spiro, and/or fused, and which contain, in addition to carbonatom(s), at least one heteroatom, such as nitrogen, oxygen or sulfur.Examples include, but are not limited to, tetrahydrofuranyl,pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl,pyrazolinyl, piperidyl, piperazinyl, indolinyl, isoindolinyl,morpholinyl, thiomorpholinyl, homomorpholinyl, homopiperidyl,homopiperazinyl, thiomorpholinyl, tetrahydropyranyl, piperidinyl,tetrahydrothienyl, homopiperidinyl, oxazolidinonyl, dihydropyrazolyl,dihydropyrrolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl,dihydrofuryl, dihydropyranyl, quinuclidinyl,2-oxa-5-azabicyclo[2.2.1]heptane, 8-oxa-3-aza-bicyclo[3.2.1]octane,3,8-diaza-bicyclo[3.2.1]octane, 2,5-diaza-bicyclo[2.2.1]heptane,3,8-diaza-bicyclo[3.2.1]octane, 3,9-diaza-bicyclo[4.2.1]nonane and2,6-diaza-bicyclo[3.2.2]nonane. Preferably, the heterocyclyl groupcontains from 3 to 10 ring atoms. More preferably, the heterocycyl groupcontains from 3 to 7 ring atoms. More preferably, the heterocyclyl groupcontains from 5 to 7 ring atoms, such as 5 ring atoms, 6 ring atoms, or7 ring atoms. Unless otherwise indicated, the foregoing heterocyclylgroups can be C-attached or N-attached where such is possible andresults in the creation of a stable structure. For example, piperidinylcan be piperidin-1-yl (N-attached) or piperidin-4-yl (C-attached). Aheterocyclyl group can also include ring systems substituted on ringcarbons with one or more —OH functional groups (which may furthertautomerize to give a ring C═O group) and/or substituted on a ringsulfur atom by one (1) or two (2) oxygen atoms to give S═O or SO₂groups, respectively.

“Substituted heterocyclyl” indicates that one or more hydrogen atoms ona heterocyclyl group has been replaced with a different atom or group ofatoms and the and the atom or group of atoms replacing the hydrogen atomis a “substituent”. Representative substituents include, but are notlimited to, halogen, (C₁-C₈)alkyl, (C₁-C₈)alkoxy,(C₁-C₈)alkoxy(C₁-C₄)alkyl, carboxyl, formyl, (C₁-C₆)acyl,halo(C₁-C₄)alkyl, halo(C₁-C₄)alkoxy, hydroxyl, nitro, cyano, amino,trifluoromethyl, mono- or di-(C₁-C₆)alkylamino, oxo, (C₆-C₁₀)aryl,(C₅-C₉)heteroaryl, (C₁-C₆)alkoxycarbonyl, (C₃-C₁₀)cycloalkyl,(C₃-C₁₀)cycloalkyloxy, (C₃-C₁₀)cycloalkyl(C₁-C₆)alkoxy,(C₂-C₉)heterocyclyl, (C₂-C₉)heterocyclyloxy,(C₂-C₉)heterocyclyl(C₁-C₄)alkoxy, (C₁-C₆)alkoxycarbonyl(C₁-C₄)alkyl,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkylsulfinyl, (C₁-C₆)alkylsulfonyl, mono-and di-(C₁-C₆)alkylaminocarbonyl, (C₁-C₆)acylthio, and (C₁-C₆)acyloxy.

“Heterocyclylalkoxyalkyl” refers to a heterocylylalkyl-O-alkyl- group.

“Heterocyclylcarbonyl” refers to a heterocyclyl-(C═O)— group.

“Heteroaryl” or “heteroaryl group” refers to (a) 5 and 6 memberedmonocyclic aromatic rings, which contain, in addition to carbon atom(s),at least one heteroatom, such as nitrogen, oxygen or sulfur, and (b)7-15 membered bicyclic and tricyclic rings, which contain, in additionto carbon atom(s), at least one heteroatom, such as nitrogen, oxygen orsulfur, and in which at least one of the rings is aromatic. Heteroarylgroups can be substituted or unsubstituted, and may be bridged, spiro,and/or fused. Examples include, but are not limited to,2,3-dihydrobenzofuranyl, 1,2-dihydroquinolinyl,3,4-dihydroisoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl,1,2,3,4-tetrahydroquinolinyl, benzoxazinyl, benzthiazinyl, chromanyl,furanyl, 2-furanyl, 3-furanyl, imidazolyl, isoxazolyl, isothiazolyl,oxadiazolyl, oxazolyl, pyridinyl, 2-, 3-, or 4-pyridinyl, pyrimidinyl,2-, 4-, or 5-pyrimidinyl, pyrazolyl, pyrrolyl, 2- or 3-pyrrolyl,pyrazinyl, pyridazinyl, 3- or 4-pyridazinyl, 2-pyrazinyl, thienyl,2-thienyl, 3-thienyl, tetrazolyl, thiazolyl, thiadiazolyl, triazinyl,triazolyl, pyridin-2-yl, pyridin-4-yl, pyrimidin-2-yl, pyridazin-4-yl,pyrazin-2-yl, naphthyridinyl, pteridinyl, phthalazinyl, purinyl,alloxazinyl, benzimidazolyl, benzofuranyl, benzofurazanyl,2H-1-benzopyranyl, benzothiadiazine, benzothiazinyl, benzothiazolyl,benzothiophenyl, benzoxazolyl, cinnolinyl, furopyridinyl, indolinyl,indolizinyl, indolyl, or 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 3H-indolyl,quinazolinyl, quinoxalinyl, isoindolyl, isoquinolinyl,10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2(7),3,5-trienyl,12-oxa-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2(7),3,5-trienyl,12-aza-tricyclo[7.2.1.0*2,7*]dodeca-2(7),3,5-trienyl,10-aza-tricyclo[6.3.2.0*2,7*]trideca-2(7),3,5-trienyl,2,3,4,5-tetrahydro-1H-benzo[d]azepinyl,1,3,4,5-tetrahydro-benzo[d]azepin-2-onyl,1,3,4,5-tetrahydro-benzo[b]azepin-2-onyl,2,3,4,5-tetrahydro-benzo[c]azepin-1-onyl,1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-onyl,2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepinyl,5,6,8,9-tetrahydro-7-oxa-benzocycloheptenyl,2,3,4,5-tetrahydro-1H-benzo[b]azepinyl,1,2,4,5-tetrahydro-benzo[e][1,3]diazepin-3-onyl,3,4-dihydro-2H-benzo[b][1,4]dioxepinyl,3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-onyl,6,7,8,9-tetrahydro-5-thia-8-aza-benzocycloheptenyl,5,5-dioxo-6,7,8,9-tetrahydro-5-thia-8-aza-benzocycloheptenyl, and2,3,4,5-tetrahydro-benzo[f][1,4]oxazepinyl. Preferably, the heteroarylgroup contains 5, 6, or 8-15 ring atoms. More preferably, the heteroarylgroup contains 5 to 10 ring atoms, such as 5, 6, 9, or 10 ring atoms. Aheteroaryl group can also include ring systems substituted on ringcarbons with one or more —OH or C═O functional groups and/or substitutedon a ring sulfur atom by one (1) or two (2) oxygen atoms to give S═O orSO₂ groups, respectively.

“Substituted heteroaryl” indicates that one or more hydrogen atoms on aheteroaryl group has been replaced with a different atom or group ofatoms and the and the atom or group of atoms replacing the hydrogen atomis a “substituent”. Representative substituents include, but are notlimited to, halogen, (C₁-C₈)alkyl, (C₁-C₈)alkoxy,(C₁-C₈)alkoxy(C₁-C₄)alkyl, carboxyl, formyl, (C₁-C₆)acyl,halo(C₁-C₄)alkyl, halo(C₁-C₄)alkoxy, hydroxyl, nitro, cyano, amino,trifluoromethyl, mono- or di-(C₁-C₆)alkylamino, oxo, (C₆-C₁₀)aryl,(C₅-C₉)heteroaryl, (C₁-C₆)alkoxycarbonyl, (C₃-C₁₀)cycloalkyl,(C₃-C₁₀)cycloalkyloxy, (C₃-C₁₀)cycloalkyl(C₁-C₆)alkoxy,(C₂-C₉)heterocyclyl, (C₂-C₉)heterocyclyloxy,(C₂-C₉)heterocyclyl(C₁-C₄)alkoxy, (C₁-C₆)alkoxycarbonyl(C₁-C₄)alkyl,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkylsulfinyl, (C₁-C₆)alkylsulfonyl, mono-and di-(C₁-C₆)alkylaminocarbonyl, (C₁-C₆)acylthio, and (C₁-C₆)acyloxy.

“Heteroarylalkyl” refers to a heteroaryl-alkyl- group.

“Halo” and “halogen” include fluoro, chloro, bromo and iodo, andfluorine, chlorine, bromine and iodine atoms.

“Trihalomethyl” refers to a —CH₃ group, the hydrogens of which have beensubstituted with halogen atoms, which may be the same or different.Representative trihalomethyl groups include CF₃, CCl₃, CBr₃ or CI₃. Apreferred trihalomethyl group is CF₃.

“Trihaloalkyl” refers to an alkyl group substituted by three halogenatoms, which may be the same or different.

“Alkoxyalkyl” or “alkoxyalkyl group” refers to an alkyl group containingan alkoxy group substituent.

“Hydroxyl”, “hydroxy”, “hydroxyl group” or “hydroxyl group” refers to an—OH group.

“Amino” or “amino group” refers to an —NH₂ group.

“Alkylamino” or “alkylamino group” refers to an alkyl-N(H)— group.

“Dialkylamino” or “dialkylamino” group refers to an (alkyl)(alkyl)N—group. In such a group the alkyl groups substituting the nitrogen may bethe same or different.

“Carboxy”, “carboxyl”, “carboxy group” or “carboxyl group” refers to a—COOH group.

“Oxo” refers to a ═O group.

“Pseudohalogen” refers to —OCN, —SCN, —CF₃, and —CN.

“Chemically stable” or “stable” refers to a compound that issufficiently robust to be isolated to a useful degree of purity from areaction mixture. The present invention is directed only to chemicallystable compounds.

“Pharmaceutical composition” refers to a composition suitable foradministration in medical or veterinary use.

When lists of alternative substituents include members which, owing tovalency requirements, chemical stability, or other reasons, cannot beused to substitute a particular group, the list is intended to be readin context to include those members of the list that are suitable forsubstituting the particular group.

“Pharmaceutically acceptable” refers to physiologically tolerablematerials, which do not typically produce an allergic or other untowardreaction, such as gastric upset, dizziness and the like, whenadministered to a mammal.

“Therapeutically effective amount” refers to an amount of a compound, ora pharmaceutically acceptable salt thereof, sufficient to inhibit, halt,or cause an improvement in a disorder or condition being treated in aparticular subject or subject population. For example in a human orother mammal, a therapeutically effective amount can be determinedexperimentally in a laboratory or clinical setting, or may be the amountrequired by the guidelines of the United States Food and DrugAdministration, or equivalent foreign agency, for the particular diseaseand subject being treated.

It should be appreciated that determination of proper dosage forms,dosage amounts, and routes of administration is within the level ofordinary skill in the pharmaceutical and medical arts, and is describedbelow.

“Subject” refers to a member of the class Mammalia. Examples of mammalsinclude, without limitation, humans, primates, chimpanzees, rodents,mice, rats, rabbits, horses, livestock, dogs, cats, sheep, and cows.

“Treatment” refers to the acute or prophylactic diminishment oralleviation of at least one symptom or characteristic associated orcaused by a disorder being treated. For example, treatment can includediminishment of several symptoms of a disorder or complete eradicationof a disorder.

“Administering” refers to the method of contacting a compound with asubject. Modes of “administering” include, but are not limited to,methods that involve contacting the compound intravenously,intraperitoneally, intranasally, transdermally, topically, viaimplantation, subcutaneously, parentally, intramuscularly, orally,systemically, and via adsorption.

II. Compounds

The present invention provides a compound of Formula I or a salt formthereof,

wherein:

-   -   E and G are independently chosen from H, C₁₋₆alkyl optionally        substituted by 1-6 R¹⁹, C₂₋₆alkenyl optionally substituted by        1-6 R¹⁹, C₂₋₆alkynyl optionally substituted by 1-6 R¹⁹,        C₆₋₁₁aryl optionally substituted by 1-6 R¹⁹, C₃₋₁₁cycloalkyl        optionally substituted by 1-6 R¹⁹, 3-15 membered heterocyclyl        optionally substituted by 1-6 R¹⁹, 5-15 membered heteroaryl        optionally substituted by 1-6 R¹⁹, —C(═O)R²⁰, —C(═O)OR²⁰,        —C(═O)NR²²R²³, —S(═O)₂R²⁰, and —S(═O)₂NR²²R²³;    -   X is N or C—R₄;    -   Y is N or C-Rid;    -   R₃ is H or C₁₋₆alkyl;    -   D is —O—, —S—, —SO—, —SO₂—, —C(═O)—, —CHOH—, —CH₂—, —NH— or        —NC₁₋₆alkyl-;    -   W is CH or N;    -   R_(a), R_(b), R_(c), R_(d), R_(1a), R_(1b), R_(1c), R_(1d), and        R₄ are independently chosen from H, C₁₋₆alkyl optionally        substituted by 1-6 R¹¹⁹, C₂₋₆alkenyl optionally substituted by        1-6 R¹¹⁹, C₂₋₆alkynyl optionally substituted by 1-6 R¹¹⁹,        C₆₋₁₁aryl optionally substituted by 1-6 R¹¹⁹, C₃₋₁₁cycloalkyl        optionally substituted by 1-6 R¹¹⁹, 3-15 membered heterocyclyl        optionally substituted by 1-6 R¹¹⁹, 5-15 membered heteroaryl        optionally substituted by 1-6 R¹¹⁹, halogen, —CN, —C(═O)R¹¹⁰,        —C(═O)OR¹¹⁰, —C(═O)NR¹¹²R¹¹³, —NC, —NO₂, —NR¹¹²R¹¹³,        NR¹¹⁴C(═O)R¹¹⁰, NR¹¹⁴C(═O)OR¹¹¹, NR¹¹⁴C(═O)NR¹¹²R¹¹³,        NR¹¹⁴S(═O)₂R¹¹, NR¹¹⁴S(═O)₂NR¹¹²R¹¹³, —OR¹¹⁰, —OCN, —OC(═O)R¹¹⁰,        —OC(═O)NR¹¹²R¹¹³, —OC(═O)OR¹¹⁰, —S(═O)_(n)R¹¹, and        —S(═O)₂NR¹¹²R¹¹³;        -   or any of R_(a) and R_(b), R_(a) and R_(d), and R_(b) and            R_(c) can, together with the atoms linking them, form a            C₆₋₁₁aryl optionally substituted by 1-6 R¹¹⁹,            C₃₋₁₁cycloalkyl optionally substituted by 1-6 R¹¹⁹, 3-15            membered heterocyclyl optionally substituted by 1-6 R¹¹⁹ or            a 5-15 membered heteroaryl optionally substituted by 1-6            R¹¹⁹;    -   R¹⁹ at each occurrence is independently chosen from C₁₋₆alkyl        optionally substituted by 1-6 R³⁹, C₂₋₆alkenyl optionally        substituted by 1-6 R³⁹, C₂₋₆alkynyl optionally substituted by        1-6 R³⁹, C₆₋₁₁aryl optionally substituted by 1-6 R³⁹,        C₃₋₁₁cycloalkyl optionally substituted by 1-6 R³⁹, 3-15 membered        heterocyclyl optionally substituted by 1-6 R³⁹, 5-15 membered        heteroaryl optionally substituted by 1-6 R³⁹, halogen, —CN,        —C(═O)R³⁰, —C(═O)OR³⁰, —C(═O)NR³²R³³, —NO₂, —NR³²R³³,        —NR³⁴C(═O)R³⁰, —NR³⁴C(═O)OR³¹, —NR³⁴C(═O)NR³²R³³, NR³⁴S(═O)₂R³¹,        NR³⁴S(═O)₂NR³²R³³, —OR³⁰, ═O, —OC(═O)R³⁰, —OC(═O)NR³²R³³,        —OC(═O)OR³⁰, —S(═O)_(n)R³⁰, and —S(═O)₂NR³²R³³;    -   R²⁰, R³⁰, R³¹, and R³⁴ at each occurrence is independently        chosen from H, C₁₋₆alkyl optionally substituted by 1-6 R⁴⁹,        C₂₋₆alkenyl optionally substituted by 1-6 R⁴⁹, C₂₋₆alkynyl        optionally substituted by 1-6 R⁴⁹, C₆₋₁₁aryl optionally        substituted by 1-6 R⁴⁹, C₃₋₁₁cycloalkyl optionally substituted        by 1-6 R⁴⁹, 3-15 membered heterocyclyl optionally substituted by        1-6 R⁴⁹, and 5-15 membered heteroaryl optionally substituted by        1-6 R⁴⁹;    -   R²², R²³, R³² and R³³ at each occurrence is independently chosen        from H, C₁₋₆alkyl optionally substituted by 1-6 R⁵⁹, C₂₋₆alkenyl        optionally substituted by 1-6 R⁵⁹, C₂₋₆alkynyl optionally        substituted by 1-6 R⁵⁹, C₆₋₁₁aryl optionally substituted by 1-6        R⁵⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-6 R⁵⁹, 3-15        membered heterocyclyl optionally substituted by 1-6 R⁵⁹, and        5-15 membered heteroaryl optionally substituted by 1-6 R⁵⁹;        -   or any R²² and R²³ and/or R³² and R³³ may form, together            with the nitrogen atom to which they are attached, a 3-15            membered heterocyclyl optionally substituted by 1-6 R⁶⁹ or a            5-15 membered heteroaryl optionally substituted by 1-6 R⁶⁹;    -   R³⁹, R⁴⁹, R⁵⁹ and R⁶⁹ at each occurrence is independently chosen        from C₁₋₆alkyl optionally substituted by 1-6 R⁷⁹, C₂₋₆alkenyl        optionally substituted by 1-6 R⁷⁹, C₂₋₆alkynyl optionally        substituted by 1-6 R⁷⁹, C₆₋₁₁aryl optionally substituted by 1-6        R⁷⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-6 R⁷⁹, 3-15        membered heterocyclyl optionally substituted by 1-6 R⁷⁹, 5-15        membered heteroaryl optionally substituted by 1-6 R⁷⁹, halogen,        —CN, —C(═O)R⁷⁰, —C(═O)OR⁷⁰, —C(═O)NR⁷²R⁷³, —NO₂, —NR⁷²R⁷³,        —NR⁷⁴C(═O)R⁷⁰, —NR⁷⁴C(═O)OR⁷¹, —NR⁷⁴C(═O)NR⁷²R⁷³,        —NR⁷⁴S(═O)₂R⁷¹, —NR⁷⁴S(═O)₂NR⁷²R⁷³, —OR⁷⁰, ═O, —OC(═O)R⁷⁰,        —OC(═O)NR⁷²R⁷³, —S(═O)_(n)R⁷⁰, and —S(═O)₂NR⁷²R⁷³;    -   R⁷⁰, R⁷¹, R⁷², R⁷³, and R⁷⁴ at each occurrence is independently        chosen from H, C₁₋₆alkyl and C₁₋₆-haloalkyl;    -   R⁷⁹ at each occurrence is independently chosen from C₁₋₆alkyl,        C₁₋₆-haloalkyl, benzyl, halogen, —CN, —C(═O)(C₁₋₆alkyl),        —C(═O)O(C₁₋₆alkyl), —C(═O)N(C₁₋₆alkyl)₂, —C(═O)OH, —C(═O)NH₂,        —C(═O)NHC₁₋₆alkyl, —NO₂, —NH₂, —NHC₁₋₆alkyl, —N(C₁₋₆alkyl)₂,        —NHC(═O)C₁₋₆alkyl, —NHS(═O)₂C₁₋₆alkyl, —OH, —OC₁₋₆alkyl, ═O,        —OC(═O)C₁₋₆alkyl, —OS(═O)₂C₁₋₆alkyl, —S(═O)₂C₁₋₆alkyl, and        —S(═O)₂N(C₁₋₆alkyl)₂;    -   R¹¹⁰, R¹¹¹, and R¹¹⁴ at each occurrence is independently chosen        from H, C₁₋₆alkyl optionally substituted by 1-6 R¹²⁹,        C₂₋₆alkenyl optionally substituted by 1-6 R¹²⁹, C₂₋₆alkynyl        optionally substituted by 1-6 R¹²⁹, C₆₋₁₁aryl optionally        substituted by 1-6 R¹²⁹, C₃₋₁₁cycloalkyl optionally substituted        by 1-6 R¹²⁹, 3-15 membered heterocyclyl optionally substituted        by 1-6 R¹²⁹, and 5-15 membered heteroaryl optionally substituted        by 1-6 R¹²⁹;    -   R¹¹² and R¹¹³ at each occurrence is independently chosen from H,        C₁₋₆alkyl optionally substituted by 1-6 R¹³⁹, C₂₋₆alkenyl        optionally substituted by 1-6 R¹³⁹, C₂₋₆alkynyl optionally        substituted by 1-6 R¹³⁹, C₆₋₁₁aryl optionally substituted by 1-6        R¹³⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-6 R¹³⁹, 3-15        membered heterocyclyl optionally substituted by 1-6 R¹³⁹, and        5-15 membered heteroaryl optionally substituted by 1-6 R¹³⁹;        -   or any R¹¹² and R¹¹³ may form, together with the nitrogen            atom to which they are attached, a 3-15 membered            heterocyclyl optionally substituted by 1-6 R¹⁴⁹ or a 5-15            membered heteroaryl optionally substituted by 1-6 R¹⁴⁹;    -   R¹¹⁹ at each occurrence is independently chosen from C₁₋₆alkyl        optionally substituted by 1-6 R¹⁵⁹, C₂₋₆alkenyl optionally        substituted by 1-6 R¹⁵⁹, C₂₋₆alkynyl optionally substituted by        1-6 R¹⁵⁹, C₆₋₁₁aryl optionally substituted by 1-6 R¹⁵⁹,        C₃₋₁₁cycloalkyl optionally substituted by 1-6 R¹⁵⁹, 3-15        membered heterocyclyl optionally substituted by 1-6 R¹⁵⁹, 5-15        membered heteroaryl optionally substituted by 1-6 R¹⁵⁹, halogen,        —CN, —C(═O)R¹⁵⁰, —C(═O)OR¹⁵⁰, —C(═O)NR¹⁵²R¹⁵³, —NC, —NO₂,        —NR¹⁵²R¹⁵³, NR¹⁵⁴C(═O)R¹⁵⁰, NR¹⁵⁴C(═O)OR¹⁵¹,        —NR¹⁵⁴C(═O)NR¹⁵²R¹⁵³, —NR¹⁵⁴S(═O)₂R¹⁵¹, NR¹⁵⁴S(═O)₂NR¹⁵²R¹⁵³,        —OR¹⁵⁰, ═O, —OC(═O)R¹⁵⁰, —OC(═O)NR¹⁵²R¹⁵³, S(═O)R¹⁵⁰, and        —S(═O)₂NR¹⁵²R¹⁵³;    -   R¹⁵⁰, R¹⁵¹, R¹⁵², R¹⁵³ and R¹⁵⁴ at each occurrence is        independently chosen from H, C₁₋₆alkyl, benzyl, and        C₁₋₆-haloalkyl;    -   R¹²⁹, R¹³⁹, R¹⁴⁹, and R¹⁵⁹ at each occurrence is independently        chosen from C₁₋₆alkyl, C₁₋₆-haloalkyl, benzyl, halogen, —CN,        —C(═O)(C₁₋₆alkyl), —C(═O)O(C₁₋₆alkyl), —C(═O)N(C₁₋₆alkyl)₂,        —C(═O)OH, —C(═O)NH₂, —C(═O)NHC₁₋₆alkyl, —NO₂, —NH₂,        —NHC₁₋₆alkyl, —N(C₁₋₆alkyl)₂, —NHC(═O)C₁₋₆alkyl,        —NHS(═O)₂C₁₋₆alkyl, —OH, —OC₁₋₆alkyl, ═O, —OC(═O)C₁₋₆alkyl,        —OS(═O)₂C₁₋₆alkyl, —S(═O)₂C₁₋₆alkyl, and —S(═O)₂N(C₁₋₆alkyl)₂;        and    -   n at each occurrence is independently chosen from 0, 1, and 2.

In one embodiment, E and G are independently chosen from H, C₁₋₆alkyloptionally substituted by 1-6 R¹⁹, C₂₋₆alkenyl optionally substituted by1-6 R¹⁹, C₂₋₆alkynyl optionally substituted by 1-6 R¹⁹, phenyloptionally substituted by 1-5 R¹⁹, C₃₋₆cycloalkyl optionally substitutedby 1-6 R¹⁹, 3-6 membered heterocyclyl optionally substituted by 1-5 R¹⁹,5-6 membered heteroaryl optionally substituted by 1-3 R¹⁹, —C(═O)R²⁰,—C(═O)OR²⁰, —C(═O)NR²²R²³, —S(═O)₂R²⁰, and —S(═O)₂NR²²R²³.

In one embodiment, E is chosen from H, C₁₋₆alkyl optionally substitutedby 1-6 R¹⁹, C₂₋₆alkenyl optionally substituted by 1-6 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-6 R¹⁹, C₆₋₁₁ aryl optionally substituted by1-6 R¹⁹, and C₃₋₁₁cycloalkyl optionally substituted by 1-6 R¹⁹.

In one embodiment, E is chosen from H, C₁₋₆alkyl optionally substitutedby 1-6 R¹⁹, C₂₋₆alkenyl optionally substituted by 1-6 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-6 R¹⁹, phenyl optionally substituted by 1-6R¹⁹, and C₃₋₆cycloalkyl optionally substituted by 1-6 R¹⁹.

In one embodiment, E is chosen from H, C₁₋₆alkyl optionally substitutedby 1-3 R¹⁹, C₂₋₆alkenyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-3 R¹⁹, phenyl optionally substituted by 1-3R¹⁹, and C₃₋₆cycloalkyl optionally substituted by 1-3 R¹⁹.

In one embodiment, E is chosen from H, C₁₋₆alkyl optionally substitutedby 1-3 R¹⁹, C₂₋₆alkenyl, C₂₋₆alkynyl optionally substituted by —OH,phenyl optionally substituted by halogen, and C₃₋₆cycloalkyl.

In one embodiment, E is chosen from H, C₁₋₆alkyl optionally substitutedby 1-3 R¹⁹, C₂₋₆alkenyl, C₂₋₆alkynyl optionally substituted by —OH,phenyl optionally substituted by halogen, and cyclohexyl.

In one embodiment, E is chosen from H, C₁₋₆alkyl optionally substitutedby 1-3 R¹⁹, C₂₋₆alkenyl, C₂₋₆alkynyl optionally substituted by —OH,phenyl optionally substituted by fluoro, and cyclohexyl.

In one embodiment, E is chosen from C₁₋₆alkyl optionally substituted byR¹⁹, phenyl, and p-fluorophenyl.

In one embodiment, E is phenyl optionally substituted by 1-5 halogen.

In one embodiment, E is C₁₋₆alkyl optionally substituted by R¹⁹.

In one embodiment, E is p-fluorophenyl.

In one embodiment, G is chosen from H, C₁₋₆alkyl optionally substitutedby 1-6 R¹⁹, C₂₋₆alkenyl optionally substituted by 1-6 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-6 R¹⁹, C₆₋₁₁aryl optionally substituted by1-6 R¹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-6 R¹⁹, and 3-15membered heterocyclyl optionally substituted by 1-6 R¹⁹.

In one embodiment, G is chosen from H, C₁₋₆alkyl optionally substitutedby 1-3 R¹⁹, C₂₋₆alkenyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-3 R¹⁹, phenyl optionally substituted by 1-3R¹⁹, C₃₋₆cycloalkyl optionally substituted by 1-3 R¹⁹, and 3-6 memberedheterocyclyl optionally substituted by 1-3 R¹⁹.

In one embodiment, G is chosen from H, C₁₋₆alkyl optionally substitutedby 1-3 R¹⁹, C₂₋₆alkenyl optionally substituted by 1-3 halogen,C₂₋₆alkynyl, phenyl optionally substituted by 1-3 halogen,C₃₋₆cycloalkyl, and 3-6 membered heterocyclyl.

In one embodiment, G is chosen from H, C₁₋₆alkyl optionally substitutedby 1-3 R¹⁹, C₂₋₆alkenyl optionally substituted by 1-3 halogen,C₂₋₆alkynyl, phenyl optionally substituted by 1-3 halogen,C₃₋₆cycloalkyl, and 6 membered heterocyclyl.

In one embodiment, G is chosen from H, C₁₋₆alkyl optionally substitutedby 1-3 R¹⁹, C₃₋₆alkenyl optionally substituted by 1-3 fluoro,C₃₋₆alkynyl, phenyl optionally substituted by 1-3 fluoro,C₃₋₆cycloalkyl, and 6 membered heterocyclyl.

In one embodiment, G is chosen from H, C₁₋₆alkyl optionally substitutedby 1-3 R¹⁹, C₃₋₆alkenyl optionally substituted by 1-3 fluoro,C₃₋₆alkynyl, phenyl optionally substituted by 1-3 fluoro,C₃₋₆cycloalkyl, and 6 membered heterocyclyl.

In one embodiment, G is chosen from H, C₁₋₆alkyl optionally substitutedby R¹⁹, C₃₋₆alkenyl optionally substituted by 2 fluoro, C₃₋₆alkynyl,phenyl optionally substituted by fluoro, C₃₋₆cycloalkyl, andtetrahydropyranyl.

In one embodiment, G is H.

In one embodiment, G is C₁₋₆alkyl optionally substituted by R¹⁹.

In one embodiment, G is C₁₋₆alkyl.

In one embodiment, G is C₃₋₆alkenyl optionally substituted by 2 fluoro.

In one embodiment, G is C₃₋₆alkynyl.

In one embodiment, G is phenyl optionally substituted by fluoro.

In one embodiment, G is p-fluorophenyl.

In one embodiment, G is C₃₋₆cycloalkyl.

In one embodiment, G is tetrahydropyranyl.

In one embodiment, X is N.

In one embodiment, X is C—R₄.

In one embodiment, Y is N.

In one embodiment, Y is CH.

In one embodiment, Y is C—R_(1d).

In one embodiment, R₃ is H.

In one embodiment, R₃ is C₁₋₆alkyl.

In one embodiment, D is —O—, —S—, —C(═O)—, —CHOH—, —CH₂—, —NH— or—NC₁₋₆alkyl-.

In one embodiment, D is —O—, —S—, —C(═O)—, —CHOH—, —CH₂—, or —NH—.

In one embodiment, D is —O—, —S—, —C(═O)—, —CHOH—, or —CH₂—.

In one embodiment, D is —O—, —C(═O)—, —CHOH—, or —CH₂—.

In one embodiment, D is —O—, —C(═O)—, —CHOH—, or —CH₂—.

In one embodiment, D is —O—.

In one embodiment, D is —C(═O)—.

In one embodiment, D is —CHOH—.

In one embodiment, D is —CH₂—.

In one embodiment, W is CH.

In one embodiment, W is N.

In one embodiment, R_(a), R_(b), R_(c), and R_(d) are independentlychosen from H, C₁₋₆alkyl optionally substituted by 1-6 R¹¹⁹, C₂₋₆alkenyloptionally substituted by 1-6 R¹¹⁹, C₂₋₆alkynyl optionally substitutedby 1-6 R¹¹⁹, C₆₋₁₁aryl optionally substituted by 1-6 R¹¹⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-6 R¹¹⁹, 3-15 memberedheterocyclyl optionally substituted by 1-6 R¹¹⁹, 5-15 memberedheteroaryl optionally substituted by 1-6 R¹¹⁹ halogen, —CN, —C(═O)R¹¹⁰,—C(═O)NR¹¹²R¹¹³, —NO₂, —NR¹¹²R¹¹³, —NR¹¹⁴C(═O)R¹¹⁰, —NR¹¹⁴C(═O)OR¹¹,—NR¹¹⁴C(═O)NR¹¹²R¹¹³, —NR¹¹⁴S(═O)₂R¹¹¹, —OR¹¹⁰, —S(═O)₂R¹¹⁰, and—S(═O)₂NR¹¹²R¹¹³; or any of R_(a) and R_(b), R_(a) and R_(d), and R_(b)and R_(c) can, together with the atoms linking them, form a C₆₋₁₁aryloptionally substituted by 1-6 R¹¹⁹, C₃₋₁₁cycloalkyl optionallysubstituted by 1-6 R¹¹⁹, 3-15 membered heterocyclyl optionallysubstituted by 1-6 R¹¹⁹ or a 5-15 membered heteroaryl optionallysubstituted by 1-6 R¹¹⁹.

In one embodiment, R_(a), R_(b), R_(c), and R_(d) are independentlychosen from H, C₁₋₆alkyl optionally substituted by 1-6 R¹¹⁹, —CN, and—OR¹⁰; or R_(a) and R_(b) can, together with the atoms linking them,form a 3-6 membered heterocyclyl optionally substituted by 1-6 R¹¹⁹.

In one embodiment, R_(a), R_(b), R_(c), and R_(d) are independentlychosen from H, C₁₋₆alkyl optionally substituted by 1-6 R¹¹⁹, —CN, and—OR¹⁰; or R_(a) and R_(b) can, together with the atoms linking them,form a 5-6 membered heterocyclyl optionally substituted by 1-6 R¹¹⁹.

In one embodiment, R_(a), R_(b), R_(c), and R_(d) are independentlychosen from H, C₁₋₆alkyl optionally substituted by 1-6 R¹¹⁹, —CN, and—OR¹¹⁰; or R_(a) and R_(b) can, together with the atoms linking them,form a 5-6 membered heterocyclyl.

In one embodiment, R_(a) is chosen from H, —CN, and —OC₁₋₆alkyl; R_(b)is chosen from H, C₁₋₆alkyl optionally substituted by 1-6 R¹¹⁹, and—OR¹¹⁰; R_(c) is chosen from H and —OC₁₋₆alkyl; and R_(d) is chosen fromH and —OC₁₋₆alkyl; or R_(a) and R_(b) can, together with the atomslinking them, form a 5-6 membered heterocyclyl.

In one embodiment, R_(a) is chosen from H, —CN, and —OC₁₋₆alkyl; R_(b)is chosen from H, C₁₋₆alkyl optionally substituted by 6-memberedheterocyclyl, and —OR¹¹⁰; R_(c) is chosen from H and —OC₁₋₆alkyl; andR_(d) is chosen from H and —OC₁₋₆alkyl; or R_(a) and R_(b) can, togetherwith the atoms linking them, form a 5-6 membered heterocyclyl.

In one embodiment, R_(a) is chosen from H, —CN, and —OC₁₋₆alkyl; R_(b)is chosen from H, C₁₋₆alkyl optionally substituted by 6-memberedheterocyclyl, —OH, —OC₁₋₆alkyl, —OCH₂phenyl, —OC₁₋₆alkyl-O—C₁₋₆alkyl;R_(c) is chosen from H and —OC₁₋₆alkyl; and R_(d) is chosen from H and—OC₁₋₆alkyl; or R_(a) and R_(b) can, together with the atoms linkingthem, form a 5-6 membered heterocyclyl.

In one embodiment, R_(a) is chosen from H, —CN, and —OC₁₋₆alkyl; R_(b)is chosen from H, C₁₋₆alkyl optionally substituted by morpholinyl, —OH,—OC₁₋₆alkyl, —OCH₂phenyl, —OC₁₋₆alkyl-O—C₁₋₆alkyl; R_(c) is chosen fromH and —OC₁₋₆alkyl; and R_(d) is chosen from H and —OC₁₋₆alkyl; or R_(a)and R_(b) together form

In one embodiment, R_(a) is chosen from H and —OC₁₋₆alkyl; R_(b) ischosen from H, C₁₋₆alkyl optionally substituted by morpholinyl, —OH,—OC₁₋₆alkyl, —OCH₂phenyl, —OC₁₋₆alkyl-O—C₁₋₆alkyl; R_(e) is H; and R_(d)is chosen from H and —OC₁₋₆alkyl; or R_(a) and R_(b) together form

In one embodiment, R_(a) is chosen from H and —OC₁₋₆alkyl; R_(b) ischosen from C₁₋₆alkyl optionally substituted by morpholinyl, —OH,—OC₁₋₆alkyl, —OCH₂phenyl, —OC₁₋₆alkyl-O—C₁₋₆alkyl; R_(c) is H; and R_(d)is chosen from H and —OC₁₋₆alkyl; or R_(a) and R_(b) together form

In one embodiment, R_(a) is —OC₁₋₆alkyl; R_(b) is chosen from H,C₁₋₆alkyl optionally substituted by morpholinyl, —OH, —OC₁₋₆alkyl,—OCH₂phenyl, —OC₁₋₆alkyl-O—C₁₋₆alkyl; R_(c) is H; and R_(d) is chosenfrom H and —OC₁₋₆alkyl; or R_(a) and R_(b) together form

In one embodiment, R_(a) is chosen from H and —OC₁₋₆alkyl; R_(b) ischosen from H and —OC₁₋₆alkyl; R_(c) is H; and R_(d) is chosen from Hand —OC₁₋₆alkyl; or R_(a) and R_(b) together form

In one embodiment, R_(a), R_(b), R_(c), and R_(d) are independentlychosen from H and —OC₁₋₆alkyl; or R_(a) and R_(b) together form

In one embodiment, R_(a) is chosen from H and —OC₁₋₆alkyl; R_(b) ischosen from H and —OC₁₋₆alkyl; R_(c) is H; and R_(d) is H; or R_(a) andR_(b) together form

In one embodiment, R_(a) is chosen from H and —OC₁₋₆alkyl; R_(b) ischosen from H and —OC₁₋₆alkyl; R_(c) is H; and R_(d) is H.

In one embodiment, R_(a) is chosen from H and —OC₁₋₃alkyl; R_(b) ischosen from H and —OC₁₋₃alkyl; R_(c) is H; and R_(d) is H.

In one embodiment, R_(c) is H; R_(d) is H; and R_(a) and R_(b) togetherform

In one embodiment, R₄ is chosen from H. C₁₋₆alkyl, and C₁₋₆haloalkyl.

In one embodiment, R₄ is chosen from H and C₁₋₆alkyl.

In one embodiment, R₄ is chosen from H and C₁₋₃alkyl.

In one embodiment, R₄ is chosen from H and methyl.

In one embodiment, R₄ is H.

In one embodiment, R₄ is C₁₋₃alkyl.

In one embodiment, R₄ is methyl.

In one embodiment, R_(1a), R_(1b), R_(1c), and R_(1d) are independentlychosen from H, C₁₋₆alkyl optionally substituted by 1-6 R¹¹⁹,C₃₋₆cycloalkyl optionally substituted by 1-6 R¹¹⁹, 3-6 memberedheterocyclyl optionally substituted by 1-6 R¹¹⁹, halogen, —CN,—NR¹¹²R¹¹³ and —OR¹¹⁰.

In one embodiment, R_(1a), R_(1b), R_(1c), and R_(1d) are independentlychosen from H, C₁₋₆alkyl optionally substituted by 1-6 R¹¹⁹,C₃₋₆cycloalkyl optionally substituted by 1-6 R¹¹⁹ halogen, —NR¹¹²R¹¹³,and —OR¹¹⁰.

In one embodiment, R_(1a), R_(1b), R_(1c), and R_(1d) are independentlychosen from H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl, halogen, —NH₂,—NHC₁₋₆alkyl₂, —N(C₁₋₆alkyl)₂, —OH, and —OC₁₋₆alkyl.

In one embodiment, R_(1a), R_(1b), R_(1c), and R_(1d) are independentlychosen from H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl, halogen,—N(C₁₋₆alkyl)₂, —OC₁₋₆alkyl.

In one embodiment, R_(1a), R_(1b), R_(1c), and R_(1d) are independentlychosen from H, C₁₋₃alkyl, C₁₋₃haloalkyl, C₃₋₆cycloalkyl, halogen, and—OC₁₋₃alkyl.

In one embodiment, R_(1a), R_(1b), R_(1c), and R_(1d) are independentlychosen from H, C₁₋₃alkyl, C₁₋₃haloalkyl, cyclopropyl, halogen, and—OC₁₋₃alkyl.

In one embodiment, R_(1a), R_(1b), R_(1c), and R_(1d) are independentlychosen from H, halogen, and —OC₁₋₃alkyl.

In one embodiment, R_(1a), R_(1b), R_(1c), and R_(1d) are independentlychosen from H, halogen, and methoxy.

In one embodiment, R_(1a), R_(1b), R_(1c), and R_(1d) are independentlychosen from H and halogen.

In one embodiment, R_(1a), R_(1b), R_(1c), and R_(1d) are independentlychosen from H and fluoro.

In one embodiment, R_(1a) and R_(1b) are independently chosen from H,C₁₋₆alkyl optionally substituted by 1-6 R¹¹⁹, C₃₋₆cycloalkyl optionallysubstituted by 1-6 R¹¹⁹ halogen, and —OR¹¹⁰; and R_(1c) and R_(1d) areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-6R¹¹⁹, halogen, —NR¹¹²R¹¹³, and —OR¹⁰.

In one embodiment, R_(1a) and R_(1b) are independently chosen from H,C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl, halogen, and —OC₁₋₆alkyl; andR¹, and R_(1d) are independently chosen from H, C₁₋₆alkyl, halogen,—N(C₁₋₆alkyl)₂, and —OC₁₋₆alkyl.

In one embodiment, R_(1a) and R_(1b) are independently chosen from H,C₁₋₃alkyl, C₁₋₃haloalkyl, C₃₋₆cycloalkyl, halogen, and —OC₁₋₃alkyl; andR_(1c) and R_(1d) are independently chosen from H, C₁₋₃alkyl, halogen,—N(C₁₋₃alkyl)₂, and —OC₁₋₃alkyl.

In one embodiment, R_(1a) and R_(1b) are independently chosen from H,C₁₋₃alkyl, C₁₋₃haloalkyl, cyclopropyl, halogen, and —OC₁₋₃alkyl; andR_(1c) and R_(1d) are independently chosen from H, C₁₋₃alkyl, halogen,—N(C₁₋₃alkyl)₂, and —OC₁₋₃alkyl.

In one embodiment, R_(1a) and R_(1b) are independently chosen from H,C₁₋₃alkyl, C₁₋₃haloalkyl, cyclopropyl, halogen, and —OC₁₋₃alkyl; andR_(1c) and R_(1d) are independently chosen from H, C₁₋₃alkyl, halogen,and —OC₁₋₃alkyl.

In one embodiment, R_(1a), R_(1c), and R_(1d) are H and R_(1b) is chosenfrom H, C₁₋₃alkyl, C₁₋₃haloalkyl, cyclopropyl, halogen, and —OC₁₋₃alkyl.

In one embodiment, R_(1a), R_(1c), and R_(1d) are H and R_(1b) is chosenfrom H, halogen, and —OC₁₋₃alkyl.

In one embodiment, R_(1a), R_(1c), and R_(1d) are H and R_(1b) is chosenfrom H and halogen.

In one embodiment, R_(1a), R_(1c), and R_(1d) are H and R_(1b) is chosenfrom H and fluoro.

In one embodiment, R_(1a), R_(1c), and R_(1d) are H and R_(1b) ishalogen.

In one embodiment, R_(1a), R_(1c), and R_(1d) are H and R_(1b) isfluoro.

In one embodiment, R¹⁹ at each occurrence is independently chosen fromC₁₋₆alkyl optionally substituted by 1-6 R³⁹, C₆₋₁₁aryl optionallysubstituted by 1-6 R³⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-6R³⁹, 3-15 membered heterocyclyl optionally substituted by 1-6 R³⁹, 5-15membered heteroaryl optionally substituted by 1-6 R³⁹, halogen, —CN,—C(═O)OR³⁰, —C(═O)NR³²R³³, —NR³²R³³, —OR³⁰, and ═O.

In one embodiment, R¹⁹ at each occurrence is independently chosen fromC₁₋₆alkyl optionally substituted by 1-6 R³⁹, phenyl optionallysubstituted by 1-6 R³⁹, C₃₋₆cycloalkyl optionally substituted by 1-6R³⁹, 3-6 membered heterocyclyl optionally substituted by 1-6 R³⁹, 5-6membered heteroaryl optionally substituted by 1-6 R³⁹, halogen, —CN,—C(═O)OR³⁰, —C(═O)NR³²R³³, —NR³²R³³, —OR³⁰, and ═O.

In one embodiment, R¹⁹ at each occurrence is independently chosen fromC₁₋₆alkyl, phenyl optionally substituted by 1-3 halogen, C₃₋₆cycloalkyl,3-6 membered heterocyclyl, 5-6 membered heteroaryl optionallysubstituted by 1-3 C₁₋₆alkyl, halogen, —CN, —C(═O)OH, —C(═O)OC₁₋₆alkyl,—C(═O)N(C₁₋₆alkyl)₂, —N(C₁₋₆alkyl)₂, —OH, —OC₁₋₆alkyl, —Obenzyl, and ═O.

In one embodiment, R¹⁹ at each occurrence is independently chosen fromC₁₋₆alkyl, phenyl optionally substituted by 1-3 halogen, C₃₋₆cycloalkyl,5-6 membered heterocyclyl, 5-6 membered heteroaryl optionallysubstituted by 1-3 C₁₋₆alkyl, halogen, —CN, —C(═O)OH, —C(═O)OC₁₋₆alkyl,—C(═O)N(C₁₋₆alkyl)₂, —C(═O)pyrrolidinyl, —C(═O)morpholinyl,—N(C₁₋₆alkyl)₂, —OH, —OC₁₋₆alkyl, —Obenzyl, and ═O.

In one embodiment, R¹⁹ at each occurrence is independently chosen fromC₃₋₆cycloalkyl and —OH.

In one embodiment, R¹⁹ at each occurrence is independently chosen fromcyclopropyl and —OH.

In one embodiment, R²⁰, R³⁰, R³¹, R³⁴, R²², R²³, R³² and R³³ at eachoccurrence is independently chosen from H, C₁₋₆alkyl, C₁₋₆halolkyl,phenyl, benzyl, C₅₋₆cycloalkyl, 5-6 membered heterocyclyl, and 5-6membered heteroaryl; or R³² and R³³ may form, together with the nitrogenatom to which they are attached, a 5-6 membered heterocyclyl or a 5-6membered heteroaryl.

In one embodiment, R²⁰, R³⁰, R³¹, R³⁴, R²², R²³, R³² and R³³ at eachoccurrence is independently chosen from H, C₁₋₆alkyl, C₁₋₆halolkyl,phenyl, benzyl, C₅₋₆cycloalkyl, 5-6 membered heterocyclyl, and 5-6membered heteroaryl.

In one embodiment, R²⁰, R³⁰, R³¹, R³⁴, R²², R²³, R³² and R³³ at eachoccurrence is independently chosen from H and C₁₋₆alkyl.

In one embodiment, R³⁹, R⁴⁹, R⁵⁹ and R⁶⁹ at each occurrence isindependently chosen from C₁₋₆alkyl, C₁₋₆haloalkyl, and benzyl.

In one embodiment, R³⁹, R⁴⁹, R⁵⁹ and R⁶⁹ at each occurrence isindependently chosen from C₁₋₆alkyl and C₁₋₆haloalkyl.

In one embodiment, R³⁹, R⁴⁹, R⁵⁹ and R⁶⁹ at each occurrence isindependently chosen from C₁₋₆alkyl.

In one embodiment, R⁷⁰, R⁷¹, R⁷², R⁷³, and R⁷⁴ at each occurrence isindependently chosen from H and C₁₋₆alkyl.

In one embodiment, R⁷⁰, R⁷¹, R⁷², R⁷³, and R⁷⁴ at each occurrence is H.

In one embodiment, R⁷⁹ at each occurrence is independently chosen fromC₁₋₆alkyl, C₁₋₆-haloalkyl, benzyl, and halogen.

In one embodiment, R⁷⁹ at each occurrence is independently chosen fromC₁₋₆alkyl and C₁₋₆-haloalkyl.

In one embodiment, R⁷⁹ at each occurrence is independently chosen fromC₁₋₆alkyl.

In one embodiment, R¹¹⁰, R¹¹¹, R¹¹², R¹¹³, and R¹¹⁴ at each occurrenceis independently chosen from H and C₁₋₆alkyl optionally substituted by1-3 R¹²⁹.

In one embodiment, R¹¹⁰, R¹¹¹, R¹¹², R¹¹³, and R¹¹⁴ at each occurrenceis independently chosen from H and C₁₋₃alkyl optionally substituted by1-3 R¹²⁹.

In one embodiment, R¹¹⁰, R¹¹¹, R¹¹², R¹¹³, and R¹¹⁴ at each occurrenceis independently chosen from H, benzyl, and C₁₋₆alkyl optionallysubstituted by —OC₁₋₃alkyl.

In one embodiment, R¹¹⁰, R¹¹¹, R¹¹², R¹¹³, and R¹¹⁴ at each occurrenceis independently chosen from H and C₁₋₃alkyl optionally substituted by—OC₁₋₃alkyl.

In one embodiment, R¹¹⁰, R¹¹¹, R¹¹², R¹¹³, and R¹¹⁴ at each occurrenceis independently chosen from H and C₁₋₃alkyl.

In one embodiment, R¹¹⁰, R¹¹¹, R¹¹², R¹¹³, and R¹¹⁴ at each occurrenceis H.

In one embodiment, R¹¹⁹ at each occurrence is independently chosen fromC₁₋₆alkyl optionally substituted by 1-6 R¹⁵⁹, 3-15 membered heterocyclyloptionally substituted by 1-6 R¹⁵⁹, and halogen.

In one embodiment, R¹¹⁹ at each occurrence is independently chosen fromC₁₋₆alkyl optionally substituted by 1-3 R¹⁵⁹, 5-6 membered heterocyclyloptionally substituted by 1-3 R¹⁵⁹, and halogen.

In one embodiment, R¹¹⁹ at each occurrence is independently chosen fromC₁₋₆alkyl, C₁₋₆haloalkyl, 5-6 membered heterocyclyl, and halogen.

In one embodiment, R¹¹⁹ at each occurrence is independently chosen from5-6 membered heterocyclyl and halogen.

In one embodiment, R¹¹⁹ at each occurrence is independently chosen from6 membered heterocyclyl and halogen.

In one embodiment, R¹¹⁹ at each occurrence is independently chosen frommorpholinyl and halogen.

In one embodiment, R¹¹⁹ at each occurrence is independently chosen frommorpholinyl and fluoro.

In one embodiment, R¹⁵⁰, R¹⁵¹, R¹⁵², R¹⁵³ and R¹⁵⁴ at each occurrence isindependently chosen from H and C₁₋₆alkyl.

In one embodiment, R¹⁵⁰, R¹⁵, R¹⁵², R¹⁵³ and R¹⁵⁴ at each occurrence isH.

In one embodiment, R¹²⁹, R¹³⁹, R¹⁴⁹, and R¹⁵⁹ at each occurrence isindependently chosen from C₁₋₆alkyl, C₁₋₆-haloalkyl, benzyl, andhalogen.

In one embodiment, R¹²⁹, R¹³⁹, R¹⁴⁹, and R¹⁵⁹ at each occurrence isindependently chosen from C₁₋₆alkyl and halogen.

In one embodiment, R¹²⁹, R¹³⁹, R¹⁴⁹, and R¹⁵⁹ at each occurrence ishalogen.

In one embodiment, R¹²⁹, R¹³⁹, R¹⁴⁹, and R¹⁵⁹ at each occurrence isC₁₋₆alkyl.

In one embodiment, n at each occurrence is 0 or 2.

In one embodiment, n at each occurrence is 0.

In one embodiment, n at each occurrence is 2.

The present invention also provides compounds of Formula II

wherein:

R_(a) is H, alkyl, halo, cyano, hydroxyl, amino, alkylamino,dialkylamino where the alkyl groups of dialkylamino may be the same ordifferent, carbamoyl, N-alkylcarbamoyl, N,N-dialkylcarbamoyl, where thealkyl groups of dialkylcarbamoyl may be the same or different,trihalomethyl, or R_(a) is OA;

R_(b) is H, alkyl, halo, cyano, hydroxyl, amino, alkylamino,dialkylamino where the alkyl groups of dialkylamino may be the same ordifferent, carbamoyl, N-alkylcarbamoyl, N,N-dialkylcarbamoyl, where thealkyl groups of dialkylcarbamoyl may be the same or different,trihalomethyl, or R_(b) is OB;

R_(c) is H, alkyl, halo, cyano, hydroxyl, amino, alkylamino,dialkylamino where the alkyl groups of dialkylamino may be the same ordifferent, carbamoyl, N-alkylcarbamoyl, N,N-dialkylcarbamoyl, where thealkyl groups of dialkylcarbamoyl may be the same or different,trihalomethyl, or R_(c) is OJ;

R_(d) is H, alkyl, halo, cyano, hydroxyl, amino, alkylamino,dialkylamino where the alkyl groups of dialkylamino may be the same ordifferent, carbamoyl, N-alkylcarbamoyl, N,N-dialkylcarbamoyl, where thealkyl groups of dialkylcarbamoyl may be the same or different,trihalomethyl, or R_(d) is OL;

where A, B, J and L, are, independently, H, alkyl, alkoxyalkyl,cycloalkyl, cycloalkoxyalkyl, heterocyclylalkyl,heterocyclylalkoxyalkyl, arylalkyl or arylalkoxyalkyl, or A and Btogether with the oxygen atoms to which they are attached form

D is O, S, SO, SO₂, C═O, C(H)OH, CH₂, NH or N-alkyl;

E is H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclyl, or heteroarylalkyl, where theheteroaryl group of heteroarylalkyl may be substituted or unsubstituted;

G is H, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclyl, alkyl or cycloalkyl, cycloalkylalkyl, alkenyl or alkynyl,where alkyl, alkenyl or cycloalkyl may be substituted by one, two orthree groups selected from the group consisting of alkanoyl, cycloalkyl,alkenyl, alkynyl, halo, hydroxyl, alkoxy, alkoxycarbonyl, heterocyclyl,aryl, substituted aryl, aryloxy, arylalkoxy, amino, alkylamino,dialkylamino, where the alkyl groups of dialkylamino may be the same ordifferent, heteroaryl, carboxyl, oxo, carbamoyl, alkylcarbamoyl,dialkylcarbamoyl, where the alkyl groups of dialkylcarbamoyl may be thesame or different, and heterocycyclylcarbonyl;

W is CH or N;

X is C—R₄ or N, where R₄ is H, OH or alkyl, where the alkyl group may besubstituted by hydroxyl, alkoxy, alkylamino, or dialkyl amino, where thealkyl groups of dialkylamino may be the same or different;

Y is N, CH or C where C may be substituted with one of the groups R₁ orR₂; and

R₁ and R₂ are, independently, H, alkyl, cycloalkyl, halo, alkoxy,trihaloalkyl, amino, alkylamino, dialkylamino, where the alkyl groups ondialkylamino may be the same or different, or heterocyclyl; and

R₃ is H, or alkyl; or

-   -   a pharmaceutically acceptable salt thereof.

A preferred embodiment of the present invention provides compounds ofFormula II wherein W is CH.

Another preferred embodiment of the present invention provides compoundsof Formula II wherein W is N.

Another preferred embodiment of the present invention provides compoundsof Formula III.

wherein:

-   -   A and B are, independently, H, alkyl, alkoxyalkyl, cycloalkyl,        cycloalkoxyalkyl, heterocyclylalkyl, heterocyclylalkoxyalkyl,        arylalkyl or arylalkoxyalkyl, or A and B together with the        oxygen atoms to which they are attached form

-   -   D is O, S, NH, or C═O;    -   E is H, alkyl, substituted alkyl, alkenyl, substituted alkenyl,        alkynyl, substituted alkynyl, cycloalkyl, aryl, substituted        aryl, heteroaryl, heterocyclyl, substituted heteroaryl, or        heteroarylalkyl, where the heteroaryl group of heteroarylalkyl        may be substituted or unsubstituted;    -   G is H, aryl, substituted aryl, heteroaryl, substituted        heteroaryl, heterocyclyl, alkyl or cycloalkyl, cycloalkylalkyl,        alkenyl or alkynyl, where alkyl, alkenyl or cycloalkyl may be        substituted by one, two or three groups selected from the group        consisting of alkanoyl, cycloalkyl, alkenyl, alkynyl, halo,        hydroxyl, alkoxy, alkoxycarbonyl, heterocyclyl, aryl,        substituted aryl, aryloxy, arylalkoxy, amino, alkylamino,        dialkylamino, where the alkyl groups of dialkylamino may be the        same or different, heteroaryl, carboxyl, oxo, carbamoyl,        alkylcarbamoyl, dialkylcarbamoyl, where the alkyl groups of        dialkylcarbamoyl may be the same or different, and        heterocycyclylcarbonyl;    -   X is C—R₄ or N, where R₄ is H or alkyl;    -   Y is N, CH or C where C may be substituted with one of the        groups R₁ or R₂; and    -   R₁ and R₂ are, independently, H, alkyl, halo, alkoxy,        trihaloalkyl, amino, alkylamino, dialkylamino, where the alkyl        groups on dialkylamino may be the same or different; or    -   a pharmaceutically acceptable salt thereof.

Another preferred embodiment of the present invention provides compoundsof Formula III wherein A and B are, independently, alkyl,heterocyclylalkyl or heterocyclylalkoxyalkyl.

Another preferred embodiment of the present invention provides compoundsof Formula III wherein A and B are, independently, alkyl.

Another preferred embodiment of the present invention provides compoundsof Formula III wherein D is O, S or NH.

Another preferred embodiment of the present invention provides compoundsof Formula III wherein D is O.

Another preferred embodiment of the present invention provides compoundsof Formula III wherein R₁ and R₂ are, independently, halo, alkoxy, alkylor H.

Another preferred embodiment of the present invention provides compoundsof Formula III wherein R₁ and R₂ are, independently, halo or alkoxy.

Another preferred embodiment of the present invention provides compoundsof Formula III wherein R₁ and R₂ are, independently, methoxy or fluoro.

Another preferred embodiment of the present invention provides compoundsof Formula III wherein X is N or CH.

Another preferred embodiment of the present invention provides compoundsof Formula III wherein X is CH.

Another preferred embodiment of the present invention provides compoundsof Formula III wherein G is alkyl where alkyl may be substituted by one,two or three groups selected from the group consisting of alkanoyl,cycloalkyl, alkenyl, alkynyl, halo, hydroxyl, alkoxy, alkoxycarbonyl,heterocyclyl, aryl, substituted aryl, aryloxy, arylalkoxy, amino,alkylamino, dialkylamino, where the alkyl groups of dialkylamino may bethe same or different, heteroaryl, carboxyl, oxo, carbamoyl,alkylcarbamoyl, dialkylcarbamoyl, where the alkyl groups ofdialkylcarbamoyl may be the same or different, andheterocycyclylcarbonyl.

Another preferred embodiment of the present invention provides compoundsof Formula III wherein E is aryl, substituted aryl or cycloalkyl.

Another preferred embodiment of the present invention provides compoundsof Formula III wherein E is substituted aryl.

Another preferred embodiment of the present invention provides compoundsof Formula III wherein A and B are, independently, alkyl; D is O, S orNH; R₁ and R₂ are, independently, halo, alkoxy, alkyl or H; X is N orCH; G is alkyl where alkyl may be substituted by one, two or threegroups selected from the group consisting of alkanoyl, cycloalkyl,alkenyl, alkynyl, halo, hydroxyl, alkoxy, alkoxycarbonyl, heterocyclyl,aryl, substituted aryl, aryloxy, arylalkoxy, amino, alkylamino,dialkylamino, where the alkyl groups of dialkylamino may be the same ordifferent, heteroaryl, carboxyl, oxo, carbamoyl, alkylcarbamoyl,dialkylcarbamoyl, where the alkyl groups of dialkylcarbamoyl may be thesame or different, and heterocycyclylcarbonyl; and E is aryl,substituted aryl or cycloalkyl.

In other preferred embodiments, the present invention provides any ofthe compounds as described in the Examples.

The present invention provides salts of the AXL and c-MET inhibitorycompounds described herein. Preferably, the salts are pharmaceuticallyacceptable. Pharmaceutically acceptable acid addition salts of thecompounds described herein include, but are not limited to, saltsderived from inorganic acids such as hydrochloric, nitric, phosphoric,sulfuric, hydrobromic, hydriodic, and phosphorus, as well as the saltsderived from organic acids, such as aliphatic mono- and dicarboxylicacids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids,alkanedioic acids, aromatic acids, and aliphatic and aromatic sulfonicacids. Such salts thus include, but are not limited to, sulfate,pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate,monohydrogenphosphate, dihydrogenphosphate, metaphosphate,pyrophosphate, chloride, bromide, iodide, acetate, trifluoracetate,propionate, caprylate, isobutyrate, oxalate, malonate, succinate,suberate, sebacate, fumarate, mandelate, benzoate, chlorobenzoate,methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate,toluenesulfonate, phenylacetate, citrate, lactate, ascorbate,pyroglutamate, maleate, tartrate, and methanesulfonate. Alsocontemplated are the salts of amino acids such as arginate, gluconate,galacturonate, and the like; see, for example, Berge et al.,“Pharmaceutical Salts,” J. of Pharmaceutical Science, 1977; 66:1-19.

The acid addition salts of basic compounds described herein may beprepared by contacting the free base form with a sufficient amount ofthe desired acid to produce the salt in the conventional manner. Thefree base form may be regenerated by contacting the salt form with abase and isolating the free base in the conventional manner. The freebase forms differ from their respective salt forms somewhat in certainphysical properties such as solubility in polar solvents, but otherwisethe salts are in general equivalent to their respective free base forpurposes of the present invention.

Pharmaceutically acceptable base addition salts of compounds describedherein are formed with metals or amines, such as alkali and alkalineearth metal hydroxides, or of organic amines. Examples of metals used ascations include, but are not limited to, sodium, potassium, magnesium,and calcium. Examples of suitable amines include, but are not limitedto, N,N′-dibenzylethylenediamine, chloroprocaine, choline,diethanolamine, ethylenediamine (ethane-1,2-diamine), N-methylglucamine,and procaine; see, for example, Berge et al., supra., 1977.

The base addition salts of acidic compounds may be prepared bycontacting the free acid form with a sufficient amount of the desiredbase to produce the salt in the conventional manner. The free acid formmay be regenerated by contacting the salt form with an acid andisolating the free acid in a conventional manner. The free acid formsdiffer from their respective salt forms somewhat in certain physicalproperties such as solubility in polar solvents, but otherwise the saltsare in general equivalent to their respective free acid for purposes ofthe present invention.

Some of the compounds in the present invention may exist asstereoisomers, including enantiomers, diastereomers, and geometricisomers. Geometric isomers include compounds of the present inventionthat have alkenyl groups, which may exist as entgegen or zusammenconformations, in which case all geometric forms thereof, both entgegenand zusammen, cis and trans, and mixtures thereof, are within the scopeof the present invention. Some compounds of the present invention havecarbocyclyl groups, which may be substituted at more than one carbonatom, in which case all geometric forms thereof, both cis and trans, andmixtures thereof, are within the scope of the present invention. All ofthese forms, including (R), (S), epimers, diastereomers, cis, trans,syn, anti, (E), (Z), tautomers, and mixtures thereof, are contemplatedin the compounds of the present invention.

The compounds to be used in the present invention can exist inunsolvated forms as well as solvated forms, including hydrated forms. Ingeneral, the solvated forms, including hydrated forms, are equivalent tounsolvated forms and are intended to be encompassed within the scope ofthe present invention.

III. Pharmaceutical Compositions

The present invention further provides pharmaceutical compositionscomprising a compound of the present invention, or a pharmaceuticallyacceptable salt thereof, together with a pharmaceutically acceptablecarrier, diluent, or excipient therefor. The pharmaceutical compositionmay contain two or more compounds of the present invention (i.e., two ormore compounds of the present invention may be used together in thepharmaceutical composition). Preferably, the pharmaceutical compositioncontains a therapeutically effective amount of at least one compound ofthe present invention. In another embodiment, these compositions areuseful in the treatment of an AXL- or c-MET-mediated disorder orcondition. The compounds of the invention can also be combined in apharmaceutical composition that also comprises compounds that are usefulfor the treatment of cancer or another AXL- or c-MET-mediated disorder.

A compound of the present invention can be formulated as apharmaceutical composition in the form of a syrup, an elixir, asuspension, a powder, a granule, a tablet, a capsule, a lozenge, atroche, an aqueous solution, a cream, an ointment, a lotion, a gel, anemulsion, etc. Preferably, a compound of the present invention willcause a decrease in symptoms or a disease indicia associated with an AXLor c-MET-mediated disorder as measured quantitatively or qualitatively.

For preparing a pharmaceutical composition from a compound of thepresent invention, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,pills, capsules, cachets, suppositories, and dispersible granules. Asolid carrier can be one or more substances which may also act asdiluents, flavoring agents, binders, preservatives, tabletdisintegrating agents, or an encapsulating material.

In powders, the carrier is a finely divided solid which is in a mixturewith the finely divided active component (i.e., compound of the presentinvention). In tablets, the active component is mixed with the carrierhaving the necessary binding properties in suitable proportions andcompacted in the shape and size desired.

The powders and tablets contain from 1% to 95% (w/w) of the activecompound (i.e., compound of the present invention). In anotherembodiment, the active compound ranges from 5% to 70% (w/w). Suitablecarriers are magnesium carbonate, magnesium stearate, talc, sugar,lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose,sodium carboxymethylcellulose, a low melting wax, cocoa butter, and thelike. The term “preparation” is intended to include the formulation ofthe active compound with encapsulating material as a carrier providing acapsule in which the active component with or without other carriers, issurrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid dosage formssuitable for oral administration.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogeneous mixture is then poured into convenient sized molds, allowedto cool, and thereby to solidify.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water/propylene glycol solutions. For parenteralinjection, liquid preparations can be formulated in solution in aqueouspolyethylene glycol solution.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavors,stabilizers, and thickening agents as desired. Aqueous suspensionssuitable for oral use can be made by dispersing the finely dividedactive component in water with viscous material, such as natural orsynthetic gums, resins, methylcellulose, sodium carboxymethylcellulose,and other well-known suspending agents.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

The pharmaceutical preparation is preferably in unit dosage form. Insuch form the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

The quantity of active component in a unit dose preparation may bevaried or adjusted from 0.1 mg to 1000 mg, preferably 1.0 mg to 100 mg,or from 1% to 95% (w/w) of a unit dose, according to the particularapplication and the potency of the active component. The compositioncan, if desired, also contain other compatible therapeutic agents.

Pharmaceutically acceptable carriers are determined in part by theparticular composition being administered, as well as by the particularmethod used to administer the composition. Accordingly, there is a widevariety of suitable formulations of pharmaceutical compositions of thepresent invention (see, e.g., Remington: The Science and Practice ofPharmacy, 20th ed., Gennaro et al. Eds., Lippincott Williams andWilkins, 2000).

A compound of the present invention, alone or in combination with othersuitable components, can be made into aerosol formulations (i.e., theycan be “nebulized”) to be administered via inhalation. Aerosolformulations can be placed into pressurized acceptable propellants, suchas dichlorodifluoromethane, propane, nitrogen, and the like.

Formulations suitable for parenteral administration, such as, forexample, by intravenous, intramuscular, intradermal, and subcutaneousroutes, include aqueous and non-aqueous, isotonic sterile injectionsolutions, which can contain antioxidants, buffers, bacteriostats, andsolutes that render the formulation isotonic with the blood of theintended recipient, and aqueous and nonaqueous sterile suspensions thatcan include suspending agents, solubilizers, thickening agents,stabilizers, and preservatives. In the practice of this invention,compositions can be administered, for example, by intravenous infusion,orally, topically, intraperitoneally, intravesically or intrathecally.The formulations of compounds can be presented in unit-dose ormulti-dose sealed containers, such as ampoules and vials. Injectionsolutions and suspensions can be prepared from sterile powders,granules, and tablets of the kind previously described.

The dose administered to a subject, in the context of the presentinvention, should be sufficient to effect a beneficial therapeuticresponse in the subject over time. The dose will be determined by theefficacy of the particular compound employed and the condition of thesubject, as well as the body weight or surface area of the subject to betreated. The size of the dose also will be determined by the existence,nature, and extent of any adverse side-effects that accompany theadministration of a particular compound in a particular subject. Indetermining the effective amount of the compound to be administered inthe treatment or prophylaxis of the disorder being treated, thephysician can evaluate factors such as the circulating plasma levels ofthe compound, compound toxicities, and/or the progression of thedisease, etc. In general, the dose equivalent of a compound is fromabout 1 g/kg to 10 mg/kg for a typical subject. Many differentadministration methods are known to those of skill in the art.

For administration, compounds of the present invention can beadministered at a rate determined by factors that can include, but arenot limited to, the LD₅₀ of the compound, the pharmacokinetic profile ofthe compound, contraindicated drugs, and the side-effects of thecompound at various concentrations, as applied to the mass and overallhealth of the subject. Administration can be accomplished via single ordivided doses.

IV. Methods of Treatment

In another aspect, the present invention provides a method of treating asubject suffering from an AXL- or c-MET-mediated disorder or conditioncomprising administering to the subject a therapeutically effectiveamount of a compound of the present invention or a pharmaceuticallyacceptable salt form thereof. In another aspect, the present inventionprovides a compound of the present invention or a pharmaceuticallyacceptable salt form thereof for use in treating a subject sufferingfrom an AXL or c-MET-mediated disorder or condition. Preferably, thecompound of the present invention or a pharmaceutically acceptable saltform thereof is administered to the subject in a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier. In anotheraspect, the present invention provides a pharmaceutical compositioncomprising a compound of the present invention or a pharmaceuticallyacceptable salt form thereof for use in treating a subject sufferingfrom an AXL- or c-MET-mediated disorder or condition. In anotherembodiment, the AXL- or c-MET-mediated condition or disorder is cancer.In another embodiment, the AXL- or c-MET-mediated disorder or conditionis the development of resistance to cancer therapies. In anotherembodiment, the AXL or c-MET-mediated condition is selected from chronicmyelogenous leukemia, chronic myeloproliferative disorder, lung cancer,prostate cancer, esophageal cancer, ovarian cancer, pancreatic cancer,gastric cancer, liver cancer, thyroid cancer, renal cell carcinoma,glioblastoma, breast cancer, acute myeloid leukemia, colorectal cancer,uterine cancer, malignant glioma, uveal melanoma, osteosarcoma and softtissue sarcoma.

The AXL- or c-MET-mediated disorder or condition can be treatedprophylactically, acutely, and chronically using compounds of thepresent invention, depending on the nature of the disorder or condition.Typically, the host or subject in each of these methods is human,although other mammals can also benefit from the administration of acompound of the present invention.

In another embodiment, the present invention provides a method oftreating a proliferative disorder in a subject in need thereof,comprising administering to the subject a therapeutically effectiveamount of a compound of the present invention or a pharmaceuticallyacceptable salt form thereof. In another aspect, the present inventionprovides a compound of the present invention or a pharmaceuticallyacceptable salt form thereof for use in treating a proliferativedisorder in a subject in need thereof. Preferably, the compound of thepresent invention or a pharmaceutically acceptable salt form thereof isadministered to the subject in a pharmaceutical composition comprising apharmaceutically acceptable carrier. In another aspect, the presentinvention provides a pharmaceutical composition comprising a compound ofthe present invention or a pharmaceutically acceptable salt form thereoffor use in treating a proliferative disorder in a subject. In certainembodiments, the proliferative disorder is AXL- or c-MET-mediated. Incertain embodiments, the proliferative disorder is cancer. In certainembodiments, the proliferative disorder is selected from chronicmyelogenous leukemia, chronic myeloproliferative disorder, lung cancer,prostate cancer, esophageal cancer, ovarian cancer, pancreatic cancer,gastric cancer, liver cancer, thyroid cancer, renal cell carcinoma,glioblastoma, breast cancer, acute myeloid leukemia, colorectal cancer,uterine cancer, malignant glioma, uveal melanoma, osteosarcoma and softtissue sarcoma.

The proliferative disorder can be treated prophylactically, acutely, andchronically using compounds of the present invention, depending on thenature of the disorder or condition. Typically, the host or subject ineach of these methods is human, although other mammals can also benefitfrom the administration of a compound of the present invention.

In therapeutic applications, the compounds of the present invention canbe prepared and administered in a wide variety of oral and parenteraldosage forms. Thus, the compounds of the present invention can beadministered by injection, that is, intravenously, intramuscularly,intracutaneously, subcutaneously, intraduodenally, or intraperitoneally.Also, the compounds described herein can be administered by inhalation,for example, intranasally. Additionally, the compounds of the presentinvention can be administered transdermally. In another embodiment, thecompounds of the present invention are delivered orally. The compoundscan also be delivered rectally, bucally or by insufflation.

The compounds utilized in the pharmaceutical method of the invention canbe administered at the initial dosage of about 0.001 mg/kg to about 100mg/kg daily. In another embodiment, the daily dose range is from about0.1 mg/kg to about 10 mg/kg. The dosages, however, may be varieddepending upon the requirements of the subject, the severity of thecondition being treated, and the compound being employed. Determinationof the proper dosage for a particular situation is within the skill ofthe practitioner. Generally, treatment is initiated with smaller dosageswhich are less than the optimum dose of the compound. Thereafter, thedosage is increased by small increments until the optimum effect underthe circumstances is reached. For convenience, the total daily dosagemay be divided and administered in portions during the day, if desired.

V. Chemistry

Unless otherwise indicated, all reagents and solvents were obtained fromcommercial sources and used as received. ¹H NMRs were obtained on aBruker Avance at 400 MHz in the solvent indicated with tetramethylsilaneas an internal standard. Analytical HPLC was run using a Zorbax RX-C8,5×150 mm column eluting with a mixture of acetonitrile and watercontaining 0.1% trifluoroacetic acid with a gradient of 10-100%. LCMSresults were obtained from a Bruker Esquire 2000 Mass Spec with theAgilent 1100 HPLC equipped with an Agilent Eclipse XDB-C8, 2×30 mm 3.5micron column. The column was at room temperature, with a run time offive (5) minutes, a flow rate of 1.0 mL/min, and a solvent mixture of10% (0.1% formic acid/water): 100% (acetonitrile/0.1% formic acid).Automated normal phase column chromatography was performed on aCombiFlash Companion (ISCO, Inc.). Reverse phase preparative HPLC wasperformed on a Gilson GX-281 equipped with Gilson 333 and 334 pumpsusing a Phenomenex 00F-4454-00-AX Gemini-NX 5μ C18 column. Meltingpoints were taken on a Mel-Temp apparatus and are uncorrected.

Synthesis

The compounds of the present invention can be synthesized using themethods described below or by using methods known to one skilled in theart of organic chemistry or variations thereon as appreciated by thoseskilled in the art. The preferred methods include, but are not limitedto or by, those described below. Unless otherwise stated, startingcompounds are of commercial origin or are readily synthesized bystandard methods well known to one skilled in the art of organicsynthesis.

The reactions are performed in solvents appropriate to the reagents, andmaterials employed are suitable for the transformations being effected.Also, in the description of the synthetic methods below, it is to beunderstood that all proposed reaction conditions, including choice ofsolvent, reaction atmosphere, reaction temperature, duration ofexperiment and workup procedures are chosen to be conditions standardfor that reaction which should be readily recognized by one skilled inthe art of organic synthesis.

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application and thescope of the appended claims. Specific chemical transformations arelisted in the ensuing schemes and one skilled in the art appreciatesthat a variety of different reagents may be used in place of thoselisted. Common replacements for such reagents can be found in, but notlimited to, texts such as “Encyclopedia of Reagents for OrganicSynthesis” Leo A. Paquette, John Wiley & Son Ltd (1995) or“Comprehensive Organic Transformations: A Guide to Functional GroupPreparations” Richard C. Larock. Wiley-VCH and “Strategic Applicationsof Named Reactions in Organic Synthesis” Kurti and Czako, Elsevier, 2005and references therein.

The examples of the present invention may be produced according tosynthesis routes as depicted in Schemes 1 to 6, and by the syntheticprocedures described herein and within the examples.

In Scheme 1, W and X are as defined herein. T is Br, Cl or I. D is OH,SH, NH₂, or NH-alkyl. D is O, S, NH, or N-alkyl. R_(a)′, R_(b)′, R_(c)′,R_(d)′, R₁′ and R₂′ are R_(a), R_(b), R_(c), R_(d), R₁ and R₂,respectively, as defined herein, or are synthetic precursors thereto. Yis N, CH or C, where C may be substituted by one of the groups R₁′ orR₂′.

Looking at Scheme 1, substituted 4-chloroquinolines or 4-bromoquinolinederivatives are known and can be synthesized as described in theliterature from properly substituted arylamines and Meldrum's acid inthe presence of trimethyl orthoformate (Bioorg. Medchem. Lett., 1997, 7,789, WO9813350, US20080004273). Alternatively properly substitutedquinolines can be synthesized from substituted acetophenones by methodsdescribed in the literature (for example J. Med. Chem. 2005, 48, 1359;EP 1153920; WO201145084). Quinazolines analogs may be synthesized byliterature methods (described in J. Med. Chem. 2005, 48, 1359; J. Med.Chem. 2006, 49, 2186; J. Med. Chem. 2010, 53, 8089). The synthesizes ofN, O, and S linker quinolines and quinazolines intermediates aredescribed in J. Med. Chem. 2005, 48, 1359. A 4-(aminophenoxy)quinolinederivative may be produced by reacting a nitrophenol derivative with the4-chloroquinoline derivative in a suitable solvent, for example,chlorobenzene, to synthesize a 4-(nitrophenoxy)-quinoline derivative ora corresponding quinazoline derivative and then reacting the4-(nitrophenoxy)quinoline derivative in a suitable solvent, for example,N,N-dimethyl formamide, ethanol or ethyl acetate in the presence of acatalyst, for example, palladium hydroxide-carbon or palladium-carbon,under a hydrogen atmosphere. The nitro group can also be reduced withzinc or iron. Alternatively, the 4-(aminophenoxy)quinoline derivativecan be produced by reacting an aminophenol derivative with the4-chloroquinoline derivative in a suitable solvent, for example,dimethyl sulfoxide or N,N-dimethyl formamide, in the presence of a base,for example, sodium hydride or potassium t-butoxide. The4-(aminophenoxy)-quinazoline derivative can be produced by dissolving anaminophenol derivative in an aqueous sodium hydroxide solution andsubjecting the solution to a two phase reaction with a solution of the4-chloroquinazoline derivative in a suitable solvent, DMF, THF, or ethylmethyl ketone, in the presence of a phase transfer catalyst, forexample, tetra-n-butylammonium chloride.

An example of the synthesis of2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acids is shown inScheme 2.

Where, in Scheme 2, DCE is dichloroethane, DIEA isdiisopropylethylamine, NaOEt is sodium ethoxide, EtOH is ethanol, DMF isdimethylformamide, C₄H₈O₂ is dioxane, THF is tetrahydrofuran, MeOH isethanol, and R—X is an alkyl halide.

Starting with a 2-aminomethylene malonate and reacting with anyappropriate aryl, heteroaryl or alkyl isocyanate producesureidomethylene-malonic acid esters. The ureidomethylene-malonic acidesters can be cyclized using a base such as KOH, NaOH or sodium ethoxidein ethanol to produce the N1-H2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid esters.Starting with an N-substituted 2-aminomethylene malonate produces an N1substituted 2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acidester. Starting with substitution on the methylene malonate, for example2-(1-aminoethylidene)-malonic acid ester or2-(1-amino-2-cyclopropyl-ethylidene)-malonic acid ester produces thecorresponding C6 substituted2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-6-methyl-5-carboxylic acid esteror2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-6-cyclopropylmethyl-5-carboxylicacid ester. The N1-H intermediate may be alkylated under standardconditions using a base, for example K₂CO₃ in a solvent such asdimethylsulfoxide or dimethylformamide to produce theN1-substituted-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acidester.

2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid esters thatare N1 and N3 unsubstituted may be mono- or dialkylated using standardconditions as outlined in Scheme 3 or Scheme 4.

a. alkyl halide, K₂CO₃, dimethylformamide, 80° C. b. 1N LiOH,tetrahydrofuran, methanol, 65° C., or 4N HCl in aqueous dioxane, 80° C.

a. R²NCO, DIEA, dichloroethane, 100° C., 6 hr. b. sodium ethoxide,ethanol, rt, 18 hr. c. R¹halide, K₂CO₃, dimethylformamide, 80° C. d. 4NHCl in aqueous dioxane, 80° C., where R¹ and R² are alkyl

Hydrolysis of the 2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid esters may be achieved under standard acid or basic hydrolysisconditions to produce the acids.

a. ethyl isocyanate, tetrahydrofuran, 0° C. b. diethylethoxymethylenemalonate, sodium ethoxide, ethanol, rt, 48 hr. c. ethylacetate/hexanes. D. 1N LiOH, methanol, tetrahydrofuran, 60° C., 18 hr.

Examples where 2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acidamides are N1 aryl or N1 heteroaryl may be synthesized as outlined inScheme 5. The synthesis of N1 4-fluorophenyl is delineated for Example91. The sequential reaction of 4-fluoroaniline with ethyl isocyanatethen diethyl ethoxymethylenemalonate produces1-ethyl-3-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid ethyl ester and3-ethyl-1-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid ethyl ester. The 1-(4-fluorophenyl) isomer is readily separated bycrystallization.3-Ethyl-1-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid is produced under basic hydrolysis and can also be synthesizedunder acid conditions, then coupled to(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenylamine to produce the N1aryl amide example 91.

3,5-Dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylic acid estersmay be synthesized as outlined in Scheme 6.

2-Oxo-malonic acid diethyl ester and 4-fluorophenyl thiosemicarbazidecondensation produced4-(4-fluorophenyl)-5-oxo-3-thioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylicacid ethyl ester. Oxidation with, for example hydrogen peroxide andacetic acid produces4-(4-fluorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylicacid ethyl ester. Alkylation under conditions described for2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid estersproduced N2-substituted4-(4-fluorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylicacid ethyl esters. N1 and or N4 unsubstituted3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylic acid ethylesters may be alkylated to produce the corresponding substituted3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylic acid ethylesters. Hydrolysis of the3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylic acid ethylesters may be achieved under acidic or basic conditions to produce3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylic acids.Coupling aniline intermediates with these acids may be achieved usingknown standard procedures HATU, HOBT or EDCI, in an appropriate solventsuch as DMF or THF or by converting the acid to the acid chloride andreacting with the amine in an inert solvent.

EXAMPLES General synthesis methods for2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acids Method A:1-cyclopropylmethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

-   -   a) 2-Aminomethylene-malonic acid diethyl ester (16.7 g, 89.2        mmol) and 4-fluorophenyl isocyanate (10.6 mL, 93.7 mmol) in        1,2-dichloroethane (25 mL, 320 mmol) was added        N,N-diisopropylethylamine (17.1 mL, 98.1 mmol) and heated at        100° C. for 6 h. The mixture was cooled on an ice bath and the        solid collected and washed with ether to give the urea (24.5 g,        85%). mp=198-200° C.; LCMS m/z=347 (M+23); ¹H NMR (DMSO) δ:        10.57 (d, 1H, J=12.3 Hz), 10.41 (s, 1H), J=12.45 Hz), 8.45 (d,        1H, J=12.5 Hz), 7.48-7.53 (m, 2H), 7.16-7.21 (m, 2H), 4.24 (q,        2H, J=7 Hz), 4.15 (q, 2H, J=7 Hz), 1.22-1.28 (m, 6H).    -   b) 2-[3-(4-Fluorophenyl)ureidomethylene]malonic acid diethyl        ester (24 g; 70 mmol) was suspended in Ethanol (100 mL) and        added 21% NaOEt in EtOH (41.7 mL, 112 mmol) drop wise at rt. The        mixture was stirred 4 h, upon which time the mixture became        thick slurry. The mixture was concentrated and the residue        partitioned between ethyl acetate (EtOAc) and 1M citric acid.        The EtOAc layer was washed with water and brine, dried over        MgSO₄ and was concentrated. The solid was triturated with        ether-hexanes (⅓) to give        3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic        acid ethyl ester as a white solid. mp 206-8° C.; LCMS m/z=279        (M+1); ¹H NMR (DMSO) δ: 12.0 (s, 1H), 8.25 (s, 1H), 7.31 (bs,        2H), 7.29 (d, 2H, J=3 Hz), 4.17 (q, 2H, J=7 Hz), 1.23 (t, 3H,        J=7 Hz).    -   c)        3-(4-Fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic        acid ethyl ester (3.50 g, 11.6 mmol), potassium carbonate (3.22        g, 23.3 mmol) and cyclopropylmethyl bromide (3.39 mL, 35.0 mmol)        in N,N-dimethylformamide (DMF) (10 mL) was heated at 65° C. for        12 h. The mixture was cooled to rt, partitioned between EtOAc        and 1N Na₂CO₃, water and brine and then dried over MgSO₄. LCMS        m/z=333 (M+1); ¹H NMR (CDCL₃): 8.42 (s, 1H), 7.16-7.19 (m, 4H),        4.35 (q, 2H, J=7 Hz), 3.74 (d, 2H, J=7 Hz), 1.35 (t, 3H, J=7        Hz), 1.25 (m, 1H), 0.72 (m, 2H), 0.42 (m, 2H).    -   d) The oil from step c was dissolved in methanol (10 mL) and        tetrahydrofuran (10 mL) and 1 M of lithium hydroxide (10.6 mL)        was added. After stirring at rt for 6 h the mixture was        concentrated and extracted with 1N Na₂CO₃ (2×). The basic layer        was acidified with 1N HCl on an ice bath and the product        collected and dried to give        1-cyclopropylmethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic        acid as a white solid. LCMS m/z=305 (M+1); ¹H NMR (DMSO) δ:        12.62 (s, 1H), 8.82 (s, 1H), 7.30-7.39 (m, 4H), 3.79 (d, 2H,        J=7.2 Hz), 1.20 (m, 1H), 0.50-0.55 (m, 2H), 0.38-0.42 (m, 2H).

Method B:3-(4-Fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

-   -   a)        3-(4-Fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic        acid ethyl ester (15 g, 54 mmol), potassium carbonate (14.9 g,        108 mmol) and isopropyl iodide (10.8 mL, 108 mmol) in        N,N-dimethylformamide (35 mL) was heated at 70° C. for 12 h. The        mixture was concentrated, dissolved in EtOAc and was filtered.        The EtOAc layer was washed with 1N Na₂CO₃, water and brine and        was concentrated. The product was crystallized from        EtOAc-ether-hexanes to give        [3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic        acid ethyl ester as a white solid (15.5 g, 90%). mp 142-4° C.;        LCMS m/z=321 (M+1), ¹H NMR (CDCl₃) δ: 8.35 (s, 1H), 7.14-7.19        (m, 4H), (4.91 (h, 1H, J=6.8 Hz), 4.35 (q, 2, J=7.2 Hz), 1.44        (d, 6H, J=7 Hz), 1.36 (t, 3H, J=7.2 Hz).    -   b)        [3-(4-Fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic        acid ethyl ester (15 g, 47 mmol) was added 4M HCl in dioxane        (18.7 mL, 216 mmol) and water (5 mL) and heated at 70° C.        overnight. The product upon cooling precipitated, additional        water (˜10 mL) was added and the product collected and dried to        give        3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic        acid as a white solid. mp 168-9° C.; LCMS m/z=293 (M+1); ¹H NMR        (DMSO) δ: 12.67 (s, 1H), 8.58 (s, 1H), 7.29-7.39 (M, 4H), 4.72        (h, 1H, J=6.8 Hz), 1.38 (d, 6H, J=6.8 Hz).

Method C.3-(4-Fluorophenyl)-1-(3-methoxypropyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid

-   -   a)        3-(4-Fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic        acid (0.25 g, 1.0 mmol), and potassium carbonate (0.55 g, 4.0        mmol) in N,N-dimethylformamide (5 mL, 60 mmol) was heated at        65° C. for 12 h. The mixture was filtered, concentrated and        diluted with EtOAc. The EtOAc solution was washed with water and        brine then dried over MgSO₄ and concentrated to give an oil.    -   b) This oil was dissolved in methanol/tetrahydrofuran (MeOH/THF)        (1:1; 5 mL) and added 3 mL 1N LiOH, then heated at 60° C. for        1 h. The cooled solution was made acidic with concentrated HCl        and the white solid collected to give 125 mg (40%) of        3-(4-fluorophenyl)-1-(3-methoxy-propyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic        acid as a white solid. LCMS m/z=323 (M+1); ¹H NMR (DMSO) δ: 12.6        (s, 1H), 8.7 (s, 1H), 7.30-7.37 (m, 4H), 3.97 (t, 2H, J=7.2 Hz),        3.39 (t, 2H, J=6.3 Hz), 3.2 (s, 3H), 1.88 (q, 2H, J=6.2 Hz).

The following 2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acidswere synthesized using methods A, B or C described above.

-   -   3-(4-Fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic        acid. LCMS m/z=251 (M+1); ¹H NMR (DMSO) δ: 12.56 (b, 1H), 12.39        (s, 1H), 8.36 (s, 1H), 7.29-7.38 (M, 4H).    -   1-Ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic        acid. mp=166-8° C.; LCMS m/z=279 (M+1); ¹H NNR (DMSO) δ: 12.6        (bs, 1H), 8.82 (s, 1H), 7.29-7.38 (m, 4H), 3.94 (q, 2H, J=7.3        Hz), 1.25 t, 3H, J=7 Hz).    -   3-(4-Fluorophenyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic        acid LCMS m/z=265 (M+1); ¹HNMR (DMSO) δ: 12.59 (s, 1H), 8.80 (s,        1H), 7.3 (m, 4H), 3.56 (s, 3H).    -   1-Allyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic        acid. LCMS m/z=291 (M+1); ¹H NMR (DMSO) δ: 1H NMR (DMSO) δ:        12.66 (s, 1H), 8.72 (s, 1H), 7.27-7.41 (m, 4H), 5.89-5.99 (m,        1H), 5.24-5.35 (m, 2H), 4.53 (m, 2H).    -   1-(3,3-Difluoroallyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic        acid. LCMS m/z=327 (M+1); 1H NMR (DMSO) δ: 12.6 (s, 1H), 8.8 (s,        1H), 7.31-7.34 (m, 4H), 4.90-4.96 (m, 1H), 4.84-4.86 (m, 1H),        4.54 (d, 2H) 4.78 (m, 1H), 4.60-4.68 (M, 1H), 4.56-4.59 (m, 1H),        4.49 (m, 1H), 4.47 (m, 1H).    -   3-(4-Fluorophenyl)-1-(3-methyl-but-2-enyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic        acid. LCMS m/z=342 (M+23); ¹H NMR (DMSO) δ: 12.6 (s, 1H), 8.7        (s, 1H), 7.30-7.38 (m, 4H), 5.3 (m, 1H), 4.49 (m, 2H), 1.7 (s,        6H).    -   3-(4-Fluorophenyl)-2,4-dioxo-1-propyl-1,2,3,4-tetrahydropyrimidine-5-carboxylic        acid. LCMS m/z=293 (M+1); 1H NMR (DMSO) δ: 12.62 (s, 1H), 8.78        (s, 1H), 7.30-7.37 (m, 4H), 3.87 (t, 2H, J=7.5 Hz), 1.67 (q, 2H,        J=7.5 Hz), 0.89 (t, 3H, J=7.5 Hz).    -   3-(4-Fluorophenyl)-1-isobutyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic        acid. LCMS m/z=307 (M+1).    -   3-(4-Fluorophenyl)-2,4-dioxo-1-pentyl-1,2,3,4-tetrahydropyrimidine-5-carboxylic        acid. LCMS m/z=321 (M+1); ¹H NMR (DMSO) δ: 12.62 (s, 1H), 8.78        (s, 1H), 7.30-7.38 (m, 4H), 3.89 (m, 2H), 1.65 (m, 2H), 1.28 (m,        4H), 0.87 (t, 3H, J=7.4 Hz).    -   1-Ethyl-3-(4-fluorophenyl)-6-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic        acid. LCMS m/z=293 (M+1); ¹H NMR (DMSO) δ: 13.36 (s, 1H),        7.28-7.33 (m, 4H), 3.96 (q, 2H, J=7 Hz), 2.57 (s, 3H), 1.21 (t,        3H, J=7 Hz).        1-(2-Ethoxyethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic        acid. LCMS m/z=323 (M+1); ¹H NMR (DMSO) δ: 12.509 (s, 1H), 8.66        (s, 1H), 7.39-7.39 (m, 4H), 4.09 (t, 2H, J=5 Hz), 3.61 (t, 2H,        J=5 Hz), 3.47 (q, 2H, J=7.2 Hz), 1.11 (t, 3H, J=7.2 Hz).    -   1-(2-Benzyloxyethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic        acid. LCMS m/z=385 (M+1); ¹H NMR (DMSO) δ: 12.59 (s, 1H), 8.72        (s, 1H), 7.31-7.34 (m, 9H), 4.52 (s, 2H), 4.15 (t, 2H, J=5 Hz),        3.68 (t, 2H, J=5 Hz).    -   3-(4-Fluorophenyl)-1-(2-isopropoxy-ethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic        acid. LCMS m/z=337 (M+1). ¹H NMR (DMSO) δ: 12.57 (s, 1H), 8.67        (s, 1H), 7.32-7.36 (m, 4H), 4.06 (br, 2H), 3.6 (br, 3H), 1.07        (d, 6H, J=6 Hz).    -   1-(3-Benzyloxypropyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic        acid. LCMS m/z=399 (M+1); ¹H NMR (DMSO) δ: 12.59 (s, 1H), 8.75        (s, 1H), 7.24-7.35 (m, 9H), 4.43 (s, 2H), 4.01 (m, 2H), 3.53 (m,        2H), 1.74 (m, 2H).    -   3-(4-Fluorophenyl)-1-(2-morpholin-4-yl-ethyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic        acid; hydrochloride. LCMS m/z=400 (M+1). ¹H NMR (DMSO) δ: 11.11        (br, 1H), 10.18 (br, 1H), 7.43 (m, 2H), 7.35 (m, 2H), 4.32 (br,        2H), 3.93 (m, 4H), 3.73-3.79 (m, 6H).    -   1-((S)-2,2-Dimethyl-1,3-dioxolan-4-ylmethyl)-3-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic        acid. LCMS m/z=365 (M+1). ¹H NMR (DMSO) δ:12.60 (s, 1H), 8.66        (s, 1H), 7.34 (m, 4H), 4.34 (br, 1H), 4.12 (m, 1H), 4.01 (m,        2H), 3.72 (m, 1H), 1.30 (s, 3H), 1.27 (s, 3H).    -   1-(2-Dimethylaminoethyl)-3-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic        acid; hydrochloride. LCMS m/z=358 (M+1); ¹H NMR (DMSO) δ: 12.4        (b, 1H), 10.3 (s, 1H), 8.76 (s, 1H), 7.3-7.42 (m, 4H), 4.3 (t,        2H, J=7 Hz), 3.4 (m, 2H), 2.8 (d, 6H),    -   3-(4-Fluorophenyl)-2,4-dioxo-1-(2-pyrrolidin-1-yl-ethyl)-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic        acid; hydrochloride. LCMS m/z=384 (M+1); ¹H NMR (DMSO) δ: 12.63        (br s, 1H), 11.01 (s, 1H), 8.82 (s, 1H), 7.45 (m, 2H), 7.34 (m,        2H), 4.29 (t, 2H, J=5.2 Hz), 3.47 (m, 4H), 3.05 (m, 2H),        1.89-2.0 (m, 4H).    -   3-(4-Fluorophenyl)-2,4-dioxo-1-(2-piperidin-1-yl-ethyl)-1,2,3,4-tetrahydropyrimidine-5-carboxylic        acid; hydrochloride. LCMS m/z=398 (M+1).        3-Cyclohexyl-1-ethyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic        acid. LCMS m/z=267 (M+1); ¹H NMR (DMSO) δ: 12.87 (s, 1H), 8.70        (s, 1H), 4.67 (m, 1H), 3.98 (m, 2H), 2.26 (m, 2H), 1.78 (m, 2H),        1.60 (m, 3H), 1.07-1.33 (m, 6H).    -   1-(3-Dimethylaminopropyl)-3-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic        acid; hydrochloride. LCMS m/z=372 (M+1).    -   3-(4-Fluorophenyl)-1-(3-morpholin-4-yl-propyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic        acid; hydrochloride. LCMS m/z=414 (M+1).    -   3-(4-Fluorophenyl)-2,4-dioxo-1-(tetrahydropyran-4-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylic        acid. LCMS m/z=335 (M+1); ¹H NMR (DMSO) δ: 12.60 (s, 1H), 8.54        (s, 1H), 7.30-7.38 (m, 4H), 4.58 (m, 1H), 3.98 (m, 2H), 3.39 (m,        2H), 2.10 (m, 2H), 1.80 (m, 2H).    -   1-(4-Benzyloxybutyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic        acid. LCMS m/z=413 (M+1); ¹H NMR (DMSO) δ:12.63 (s, 1H), 8/79        (s, 1H), 7.27-7.40 (m, 4H), 4.46 (m, 2H), 3.92 (m, 2H), 3.40 (m,        2H), 1.60-1.74 (m, 2H), 1.40-1.48 (m, 2H).

1-Cyclobutyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid. LCMS m/z=305 (M+1); ¹H NMR (DMSO) δ: 12.64 (s, 1H), 8.82 (s,0.5H), 8.52 (s, 0.5H), 7.30-7.39 (m, 4H), 4.74 (m, 0.5H), 3.78 (m,0.5H), 2.29-2.40 (m, 2H), 1.75 (m, 1H), 1.22 (m, 0.5), 0.40-0.54 (m,1.5H) NMR shows rotamers.

-   -   3-(4-Fluorophenyl)-2,4-dioxo-1-prop-2-ynyl-1,2,3,4-tetrahydropyrimidine-5-carboxylic        acid. LCMS m/z=289 (M+1).    -   3-(4-Fluorophenyl)-1-(2-imidazol-1-yl-ethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic        acid. LCMS m/z=345 (M+1).    -   3-(4-Fluorophenyl)-2,4-dioxo-1-(2-pyrazol-1-yl-ethyl)-1,2,3,4-tetrahydropyrimidine-5-carboxylic        acid. LCMS m/z=345 (M+1).    -   3-(4-Fluorophenyl)-2,4-dioxo-1-phenethyl-1,2,3,4-tetrahydropyrimidine-5-carboxylic        acid. LCMS m/z=355 (M+1).    -   1-(2-[1,3]Dioxolan-2-yl-ethyl)-3-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic        acid. LCMS m/z=351 (M+1).

1-Diethylcarbamoylmethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid amide. LCMS m/z=364 (M+1).

-   -   3-(4-Fluoro-phenyl)-1-(2-morpholin-4-yl-2-oxo-ethyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic        acid amide. LCMS m/z=376 (M+1).    -   3-(4-Fluorophenyl)-2,4-dioxo-1-[2-(2-oxo-pyrrolidin-1-yl)-ethyl]-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic        acid. LCMS m/z=362 (M+1).    -   1-(2-Fluoroethyl)-3-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic        acid. LCMS m/z=397 (M+1).    -   1-tert-Butoxycarbonylmethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic        acid. LCMS m/z=365 (M+1).    -   3-(4-Fluoro-phenyl)-1-oxazol-2-ylmethyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic        acid. LCMS m/z=332 (M+1).    -   3-(4-Fluoro-phenyl)-2,4-dioxo-1-(tetrahydrofuran-2-ylmethyl)-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic        acid. LCMS m/z=335 (M+1).    -   3-(4-Fluoro-phenyl)-2,4-dioxo-1-(tetrahydro-pyran-4-ylmethyl)-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic        acid. LCMS m/z=349 (M+1).    -   3-(4-Fluoro-phenyl)-1-(2-methyl-thiazol-4-ylmethyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic        acid. LCMS m/z=362 (M+1).    -   1-Cyclopentyl-3-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic        acid. LCMS m/z=319 (M+1).    -   1-Benzyl-3-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic        acid amide. LCMS m/z=340 (M+1).    -   3-(4-Fluorophenyl)-1-[2-(2-fluorophenyl)-ethyl]-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic        acid amide. LCMS m/z=372 (M+1).    -   3-(4-Fluorophenyl)-1-[2-(4-fluoro-phenyl)-ethyl]-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic        acid amide. LCMS m/z=372 (M+1).    -   1-(2-Cyclohexyl-ethyl)-3-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic        acid. LCMS m/z=360 (M+1).    -   3-(4-Fluorophenyl)-2,4-dioxo-1-(3-phenylpropyl)-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic        acid. LCMS m/z=369 (M+1).    -   3-(4-Fluorophenyl)-2,4-dioxo-1-(2-oxo-2-pyrrolidin-1-yl-ethyl)-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic        acid. LCMS m/z=362 (M+1).    -   1-Dimethylcarbamoylmethyl-3-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic        acid. LCMS m/z=336 (M+1).    -   1-(1-Dimethylcarbamoyl-2-oxo-propyl)-3-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic        acid. LCMS m/z=378 (M+1).

Example 1

1-Ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]amide Step a.4-(6,7-Dimethoxyquinolin-4-yloxy)-3-fluorophenylamine

Sodium hydride (60% disp. in mineral oil; 1.3 g, 33.5 mmol) was added to4-amino-2-fluoro-phenol in dry N,N-dimethylformamide (50 mL) and stirredat rt for 30 min under an atmosphere of nitrogen. Then solid4-chloro-6,7-dimethoxyquinoline (5.0 g, 22.4 mmol) was added and thereaction stirred at 100° C. for 30 h. The mixture was concentrated,dissolved in EtOAc (100 mL) and washed with 1N Na₂CO₃, water and brine,then dried over MgSO₄. The product was chromatographed on silica gel (5%methanol/dichloromethane (MeOH/DCM)) to give a tan solid 4.9 g, 70%.mp=172-5° C.; LCMS m/z=315 (M+1); ¹H NMR (DMSO) δ: 8.48 (d, 1H, J=5.4Hz), 7.50 (s, 1H), 7.38 (s, 1H), 7.07 (t, 1H, J=8.6 Hz), 6.53, 6.56 (dd,1H, J=2.6, 13.4 Hz), 6.45, 6.47 (dd, 1H, J=2, 8 Hz), 6.38, 6.39 (dd, 1H,J=1, 5.4 Hz), 5.48 (s, 2H), 3.94 (s, 6H).

Step b. N,N,N′,N-Tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (HATU) (0.072 g, 0.19 mmol) and1-ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (0.053 g, 0.19 mmol) in N,N-dimethylformamide (2 mL) was addedN,N-diisopropylethylamine (0.055 mL, 0.32 mmol). After 15 min stirringat rt, 4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenylamine (0.05 g,0.2 mmol) was added. The reaction was stirred at rt for 12 h, dilutedwith EtOAc (25 mL), then washed with 1N Na₂CO₃, water and brine and thendried over MgSO4. The product was crystallized from MeOH to give 75 mg(68%) as a white solid. mp=151-4° C.; LCMS m/z=575 (M+1); ¹H NMR (DMSO)δ: 11.04 (s, 1H), 8.89 (s, 1H), 8.47 (d, 1H, J=5.4 Hz), 7.98, 8.01 (dd,1H, J=2.3, 12.6 Hz), 7.52-7.56 (m, 2H), 7.33-7.46 (m, 6H), 6.47 (d, 1H,J=5.4 Hz), 4.01 (q, 2H, J=7 Hz), 3.98 (d, 6H), 13.0 (t, 3H, J=7 Hz).

The following compounds were synthesized using procedures similar tothose for Example 1.

Example 2

3-(4-Fluorophenyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluoro-phenyl]-amide.mp=158-60° C.; LCMS m/z=561 (M+1); ¹H NMR (DMSO) δ: 11.03 (s, 1H), 8.9(s, 1H), 8.48 (d, 1H, J=6 Hz), 7.99. 8.01 (dd, 1H, J=3, 12 Hz), 7.52 (m,2H), 7.36-7.43 (m, 6H), 6.46 (d, 1H, J=6 Hz), 3.92 (s, 3H), 3.94 (s,3H), 3.54 (s, 3H).

Example 3

3-(4-Fluorophenyl)-1-(2-methoxyethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide.mp=118-21° C.; LCMS m/z=605 (M+1); ¹H NMR (DMSO) δ: 11.0 (s, 1H), 8.74(, s, 1H), 8.47 (d, 1H, J=6 Hz), 7.99, 8.01 (dd, 1H, J=3, 12 Hz),7.52-7.55 (m, 2H), 7.33-7.46 (m, 6H), 6.48 (d, 1H, J=6 Hz), 4.17 (t, 2H,J=5 Hz), 3.94 (s, 3H), 3.95 (s, 3H), 3.16 (t, 2H, J=5 Hz).

Example 4

1-(2-Ethoxyethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide.mp=128-30° C.; LCMS m/z=619 (M+1); 1H NMR (DMSO) δ: 11.0 (s, 1H), 8.76(s, 1H), 8.47 (d, 1H, J=5.4 Hz), 7.98-8.01 (dd, 1H, J=2.4, 12 Hz),7.52-7.55 (m, 2H), 7.40-7.46 (m, 4H), 7.34-7.38 (m, 2H), 6.48 (d, 1H,J=5 Hz), 4.16 (t, 2H, J=5 Hz), 3.94, 3.95 (ss, 6H), 3.65 (t, 2H, J=5Hz), 3.51 (q, 2H, J=6.6 Hz), 1.13 (t, 3H, J=6.6 Hz).

Example 5

3-(4-Fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide.mp=146-48° C.; LCMS m/z=589 (M+1); ¹H NMR (DMSO) δ: 11.9 (s, 1H), 8.68(s, 1H), 8.48 (d, 1H, J=5.2 Hz), 7.99, 8.02 (dd, 1H, J=2.4, 12.4 Hz),7.52-7.55 (m, 2H), 7.33-7.46 (m, 6H), 6.47 (d, 1H, J=5.2 Hz), 4.78 (m,1H, J=7 Hz), 3.94 (ss, 6H), 1.43 (d, 6H, J=6.7 Hz).

Example 6

1-Cyclopropylmethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide. mp=146-9°C.; LCMS (m/z=601 (M+1); ¹H NM (DMSO) δ: 11.0 (s, 1H), 8.9 (s, 1H), 8.47(d, 1H, J=5.2 Hz), 8.0, 8.02 (dd, 1H, J=2.3, 12 Hz), 7.52-7.55 (m, 2H),7.34-7.46 (m, 6H), 6.47 (m, 1H, J=5.2 Hz), (3.94, ss, 6H), 3.86 (d, 1H,J=7.2 Hz), 1.25 (m, 1H), 0.57 (m, 2H), 0.44 (m, 2H).

Example 7

3-(4-Fluorophenyl)-1-(3-methoxypropyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide. mp=126-7°C.; LCMS m/z=619 (M+1); ¹H NMR (DMSO) δ: 11.0 (s, 1H), 8.8 (s, 1H), 8.47(d, 1H, J=5.6 Hz), 7.99, 8.02 (dd, 1H, J=3.2, 13 Hz), 7.52-7.55 (m, 2H),7.34-7.46 (m, 6H), 6.46 (d, 1H, J=5.2 Hz), 4.40 (t, 2H, J=7 Hz), 3.94(ss, 6H), 3.42 (t, 2H, J=6.6 Hz), 3.24 (s, 3H), 1.191 (m, 2H).

Example 8

3-(4-Fluorophenyl)-1-isobutyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide.mp=136-40° C.; LCMS m/z=603 (M+1); ¹H NMR (DMSO) δ: 11.0 (s, 1H), 8.81(s, 1H), 8.48 (d, 1H, J=5.2 Hz), 8.0 (dd, 1H, J=2.2, 12 Hz), 7.52-7.55(m, 2H), 7.33-7.46 (m, 6H), 6.47 (d, 1H, J=5.2 Hz), 3.94 (ss, 6H), 3.82(d, 2H, J=7 Hz), 2.05 (m, 1H), 0.93 (d, 6H, J=7 Hz).

Example 9

1-Allyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide. mp128-30° C.; LCMS m/z=587 (M+1); 1H NMR (DMSO) δ: 11.0 (s, 1H), 8.80 (s,1H), 8.48 (d, 1H, =5.2 Hz), 7.98, 8.02 (dd, 1H, J=2.5, 13 Hz), 7.53-7.55(m, 1H), 7.52 (s, 1H), 7.34-7.46 (m, 6H), 6.47 (d, 1H, J=4.7 Hz),5.94-6.02 (m, 1H), 5.36, 5.40 (dd, 1H, J=1.5. 17 Hz), 5.27, 5.30 (dd,1H, J=1.5, 10 Hz), 4.62 (d, 2H, J=5.5 Hz), 3.94, 3.95 (ss, 6H).

Example 10

1-(2-Benzyloxyethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide. mp>102°C. (dec); LCMS m/z=681 (M+1); 1H NMR (DMSO) δ: 11.0 (s, 1H), 8.83 (s,1H), 8.48 (d, 1H, J=5.3 Hz), 7.99, 8.02 (dd, 1H, J=2.4, 12.8 Hz), 7.54,7.56 (dd, 1H, J=1.4, 8.8 Hz), 7.52 (s, 1H), 7.44 (t, 1H, J=8.8 Hz),7.33-7.41 (m, 9H), 7.30 (m, 1H), 6.47 (d, 1H, J=5 Hz), 4.55 (s, 2H),4.22 (t, 2H, J=4.7 Hz), 3.94, 3.95 (ss, 6H), 3.72 (t, 2H, J=4.8 Hz).

Example 11

3-(4-Fluorophenyl)-2,4-dioxo-1-propyl-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide. mp=134-6°C.; LCMS m/z=589 (M+1); ¹H NMR (DMSO) δ: 11.0 (s, 1H), 8.86 (s, 1H),8.47 (d, 1H, J=5.3 Hz), 7.98, 8.02 (dd, 1H, J=2.2, 12.6 Hz), 7.52-7.55m, 2H), 7.40-7.46 (m, 4H), 7.34-7.38 (m, 2H), 6.47 (d, 1H, J=5.2 Hz),3.92-3.97 (m, 8H), 1.71 (h, 2H, J=7.2 Hz), 0.93 (t, 3H, J=7.2 Hz).

Example 12

3-(4-Fluorophenyl)-1-(2-isopropoxyethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide. mp=138-9°C.; LCMS m/z=633 (M+1); 1H NMR (DMSO) δ: 11.00 (s, 1H), 8.78 (s, 1H),8.47 (d, 1H, J=4.7 Hz), 7.99 (d, 1H, J=13 Hz), 7.49-7.56 (m, 2H),7.38-7.46 (m, 6H), 6.47 (d, 1H, J=4.6 Hz), 4.12 (m, 2H), 3.94 (d, 6H),3.65 (m, 3H), 1.10 (d, 6H, J=6 Hz).

Example 13

1-(3-Benzyloxypropyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluoro phenyl]-amide.mp=94-96° C.; LCMS m/z=695 (M+1); ¹H NMR (DMSO) δ: 11.00 (s, 1H), 8.83(s, 1H), 8.47 (d, 1H, J=5 Hz), 7.98, 8.01 (dd, J=2.4, 12.6 Hz),7.53-7.59 (m, 1H), 7.52 (s, 1H), 7.42-7.46 (m, 1H), 7.40 (s, 1H),7.30-7.34 (m, 8H), 7.25-7.28 (m, 1H), 6.47 (dd, 1H, J=1, 5.2 Hz), 4.46(s, 2H), 4.09 (t, 2H, J=7 Hz), 3.94 (d, 6H), 3.59 (t, 2H, J=5.8 Hz),1.99 (t, 2H, J=6.4 Hz).

Example 14

1-(3,3-Difluoro-allyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide.mp=128-30° C.; LCMS m/z=623 (M+1); ¹H NMR (DMSO) δ: 11.0 (s, 1H), 8.9(s, 1H), 8.48 (d, 1H, J=5.5 Hz), 8.0, 7.98 (dd, 1H, J=2, 12.8 Hz),7.52-7.56 (m, 2H), 7.34-7.46 (m, 6H), 6.46 (d, 1H, J=5 Hz), 4.88-4.99(m, 1H), 4.62 (d, 2H, J=8 Hz), 3.94 (s, 6H).

Example 15

3-(4-Fluorophenyl)-1-(3-methyl-but-2-enyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide.mp=119-121° C.; LCMS m/z=615 (M+1); ¹H NMR (DMSO) δ: 11.0 (s, 1H), 8.789 (s, 1H), 8.47 (d, 1H, J=5.2 Hz), 8.0 (d, 1H, J=13 Hz), 7.52-7.54 (m,2H), 7.33-7.45 (m, 6H), 6.47 (d. 1H. J=5.2 Hz), 5.34 (m, 1H), 4.56 (d,1H, J=6.8 Hz), 3.94 (s, 6H), 1.76 (s, 3H), 1.74 (s, 3H).

Example 16

3-(4-Fluorophenyl)-1-(2-morpholin-4-yl-ethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluoro phenyl]-amide.mp=124-6° C.; LCMS m/z=660 (M+1); ¹H NMR (CDCl₃) δ: 10.9 (s, 1H), 8.65(s, 1H), 8.49 (d, 1H, J=5.3 Hz), 7.87, 7.90 (dd, 1H, J=2.4, 12.4 Hz),7.57 (s, 1H), 7.42 (s, 1H), 7.18-7.29 (m, 6H), 6.42 (dd, 1H, J=0.5, 5.2Hz), 4.05-4.08 (m, 8H), 3.72 (t, 4H, J=4.7 Hz), 2.73 (t, 2H, J=5.7 Hz),2.56 (m, 4H).

Example 17

3-(4-Fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide. mp=276-8°C.; LCMS m/z=547 (M+1); ¹H NMR (DMSO) δ: 12.4 (bs, 1H), 11.0 (s, 1H),8.45 (s, 2H), 7.99 (d, 1H, J=12 Hz), 7.52 (s, 2H), 7.35-7.40 (m, 6H),6.4 (s, 1H), 3.9 (s, 6H).

Example 18

Step a. 4-(6,7-Dimethoxyquinolin-4-yloxy)-phenylamine

4-(6,7-Dimethoxyquinolin-4-yloxy)phenylamine was synthesized using themethods for Example 1

step a. LCMS m/z=297 (M+1); ¹H NMR (DMSO) δ: 8.42 (d, 1H, J=5.3 Hz),7.50 (s, 1H), 7.36 (s, 1H), 7.91 (d, 2H, J=8 Hz), 6.67 (d, 2H, J=8 Hz),6.36 (d, 1H, J=5.3 Hz), 5.14 (s, 2H), 3.93 (s, 6H).

Step b.3-(4-Fluorophenyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid [4-(6,7-dimethoxyquinolin-4-yloxy)-phenyl]-amide. mp=143-5° C.;LCMS m/z=543 (M+1); ¹H NMR (DMSO) δ: 10.92 (s, 1H), 8.85 (s, 1H), 8.46(d, 1H, J=5.2 Hz), 7.80 (d, 2H, J=9 Hz), 7.50 (s, 1H), 7.34-7.42 (m,5H), 7.25 (d, 2H, J=9 Hz), 6.47 (d, 1H, J=5.2 Hz), 3.94 (s, 3H), 3.92(s, 3H), 3.53 (s, 3H).

Example 19

1-(2-Benzyloxyethyl)-3-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid [4-(6,7-dimethoxyquinolin-4-yloxy)-phenyl]-amide. mp=163-4° C.;LCMS m/z=663 (M+1); 1H NMR (DMSO) δ: 10.89 (s, 1H), 8.81 (s, 1H), 8.47(d, 1H, J=5.6 Hz), 8.80 (d, 2H, J=9 Hz), 7.50 (s, 1H), 7.25-7.41 (m,12H), 6.49 (d, 1H, J=5.8 Hz), 4.56 (s, 2H), 4.21 (t, 2H, J=5 Hz), 3.94(s, 3H), 3.92 (s, 3H), 3.72 (t, 2H, J=5 Hz).

Example 20

1-(2-Dimethylaminoethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide. mp (HClsalt): 208-10° C.; LCMS m/z=618 (M+1); ¹H NMR (DMSO) δ:11.18 (s, 1H),10.77 (s, 1H), 8.94 (s, 1H), 8.81 (d, 1H, J=6.6 Hz), 8.11, 8.08 (dd, 1H,J=2, 14 Hz), 7.74 (s, 1H), 7.65 (m, 2H), 7.50-7.60 (m, 3H), 7.37 (m,2H), 6.95 (d, 1H, J=6.5 Hz), 4.39 (t, 1H, J=5.8 Hz), 4.04 (s, 3H), 4.03(s, 3H), (2.82 (d, 6H).

Example 21

1-(3-Benzyloxypropyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid [4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-amide. mp=100-104° C.;LCMS m/z=677 (M+1); ¹H NMR (DMSO) δ: 10.90 (s, 1H), 8.81 (s, 1H), 8.47(d, 1H, J=5 Hz), 7.80 (d, 2H, J=8.8 Hz), 7.50 (s, 1H), 7.40 (s, 1H),7.25-7.33 (m, 11H), 6.49 (d, 1H, J=5.6 Hz), 4.45 (s, 2H), 4.08 (t, 2H,J=6.4 Hz), 3.94 (s, 3H), 3.92 (s, 3H), 3.56 (t, 2H, J=5.6 Hz), 1.98 (m,2H).

Example 22

1-(3-Benzyloxypropyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid [4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]-amide. mp 93-96°C.; LCMS m/z=695 (M+1); ¹H NMR (DMSO) δ: 11.13 (s, 1H), 8.85 (s, 1H),7.46-8.51 (m, 2H), 7.47 (s, 1H), 7.39-7.42 (m, 2H), 7.25-7.34 (m, 9H),7.18 (d, 1H, J=10 Hz), 6.59 (d, 1H, J=5.3 Hz), 4.50 (s, 2H), 4.09 (t,2H, J=6.5 Hz), 3.94 (s, 3H), 3.92 (s, 3H), 3.56 (t, 2H, J=6 Hz), 1.99(q, 2H, J=6.2 Hz).

Example 23

3-(4-Fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid [4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-amide. mp=253-6° C.; LCMSm/z=571 (M+1); ¹H NMR (DMSO) δ: 10.93 (s, 1H), 8.67 (s, 1H), 8.47 (d,1H, J=5.3 Hz), 7.78-7.82 (m, 2H), 7.49 (s, 1H), 7.33-7.45 (m, 5H),7.23-7.27 (m, 2H), 6.48 (d, 1H, J=5.3 Hz), 4.77 (q, 1H, J=7 Hz), 3.94(s, 3H), 3.92 (s, 3H), 1.42 (d, 6H, J=7.4 Hz).

Example 24

3-(4-Fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid [4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-amide. mp=211-3° C.; LCMSm/z=529 (M+1); ¹H NMR (DMSO) δ: 12.36 (s, 1H), 10.90 (s, 1H), 8.46 (d,1H, J=5.3 Hz), 8.43 (s, 1H), 7.77-7.80 (m, 2H), 7.49 (s, 1H), 7.39-7.43(m, 3H), 7.32-7.37 (m, 2H), 7.22-7.25 (m, 2H), 6.47 (d, 1H, J=5.3 Hz),3.94 (s, 3H), 3.92 (s, 3H).

Example 25

3-Cyclohexyl-1-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide. mp 244-6°C.; LCMS m/z=563 (M+1); ¹H NMR (DMSO) δ: 11.22 (s, 1H), 8.73 (s, 1H),8.48 (d, 1H, J=5.2 Hz), 7.99, 8.03 (dd, 1H, J=2.6, 12.6 Hz), 7.53-7.57(m, 2H), 7.41-7.47 (m, 2H), 6.48 (d, 1H, J=5.2 Hz), 4.7 (m, 1H),3.92-3.98 (m, 8H), 2.32 (m, 3H), 1.80 (m, 2H), 1.62 (m, 3H), 1.29 (m,2H), 1.25 (m, 3H).

Example 26

3-(4-Fluorophenyl)-2,4-dioxo-1-(2-pyrrolidin-1-yl-ethyl)-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluoro phenyl]-amide.mp=118-120° C.; LCMS m/z=644 (M+1); ¹H NMR (DMSO) δ: 11.00 (s, 1H), 8.79(s, 1H), 8.47 (d, 1H, J=5.2 Hz), 8.01, 7.98 (dd, 1H, J=2.3, 13 Hz),7.52-7.55 (m, 2H), 7.33-7.45 (m, 6H), 6.46 (dd, 1H, J=1, 5.3 Hz), 4.08(t, 2H, J=6.3 Hz), 3.94 (d, 6H), 2.73 (t, 2H, J=6 Hz), 2.54 (m, 4H),1.70 (m, 4H).

Example 27

3-(4-Fluorophenyl)-2,4-dioxo-1-(2-piperidin-1-yl-ethyl)-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide.mp=137-40° C.; LCMS m/z=658 (M+1); ¹H NMR (DMSO) δ: 11.00 (s, 1H), 8.78(s, 1H), 8.47 (d, 1H, J=5.5 Hz), 7.97, 8.01 (dd, 1H, J=2.3, 13 Hz),7.50-7.56 (m, 2H), 7.34-7.46 (m, 6H), 6.46 (d, 1H, J=5.5 Hz), 4.06 (t,2H, J=5.5 Hz), 3.94 (s, 6H), 2.55 (m, 2H), 2.44 (b, 4H), 1.49 (m, 4H),1.39 (m, 2H).

Example 28

1-Ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid [4-(6,7-dimethoxyquinolin-4-yloxy)-phenyl]-amide. mp=282-4° C.;LCMS m/z=557 (M+1); ¹H NMR (DMSO) δ: 10.92 (s, 1H), 8.87 (s, 1H), 8.47(d, 1H, J=5.4 Hz), 7.80 (m, 2H, J=8 Hz), 7.49 (s, 1H), 7.33-7.44 (m,5H), 7.24-7.26 (m, 2H), 6.48 (d, 1H, J=5.2 Hz), 4.01 (q, 2H, J=7.1 Hz),3.94 (s, 3H), 3.92 (s, 3H), 1.29 (t, 3H, J=7.1 Hz).

Example 29

1-Cyclobutyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide. mp148-50° C.; LCMS m/z=601 (M+1); ¹H NMR (DMSO) δ: 11.02 (s, 1H), 8.91 (s,0.4H), 8.64 (s, 0.6H), 8.48 (d, 1H, J=5.4 Hz), 7.99, 8.03 (dd, 1H,J=2.2, 13 Hz), 7.52-7.55 (m, 2H), 7.33-7.46 (m, 6H), 6.47 (d, 1H, J=5.4Hz), 3.94 (d, 6H), 4.8 (m, 0.6H), 3.8 (m, 0.4H), 2.32-2.46 (m, 3H),1.74-1.83 (m, 1H), 1.23-1.27, 0.54-0.57 (m, 1H), 0.43-0.46 (m, 1H).

Example 30

3-(4-Fluorophenyl)-2,4-dioxo-1-(tetrahydropyran-4-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluoro phenyl]-amide.mp=164-167° C.; LCMS m/z=631 (M+1); ¹H NMR (DMSO) δ: 11.0 (s, 1H), 8.65(s, 1H), 8.48 (d, 1H, J=5.3 Hz), 7.99, 8.02 (dd, 1H, J=2.5, 13 Hz),7.52-7.56 (m, 2H), 7.34-7.46 (m, 6H), 6.48 (d, 1H, J=5 Hz), 4.64 (m,1H), 3.98-4.02 (m, 2H), 3.94 (d, 6H), 3.45 (m, 2H), 1.99-2.09 (m, 2H),1.86-1.89 (m, 2H).

Example 31

1-Ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid [5-(6,7-dimethoxyquinolin-4-yloxy)-pyridin-2-yl]-amide wassynthesized starting with5-(6,7-dimethoxyquinolin-4-yloxy)-pyridin-2-ylamine. mp=172-4° C.; LCMSm/z=558 (M+1); ¹H NMR (DMSO) δ: 11.39 (s, 1H), 8.93 (s, 1H), 8.48 (d,1H, J=5.2 Hz), 8.35-8.38 (m, 2H), 7.84, 7.88 (dd, 1H, J=2.3, 9.3 Hz),7.52 (s, 1H), 7.33-7.44 (m, 5H), 6.54 (d, 1H, J=5.2 Hz). 4.02 (q, 2H,J=7.4 Hz), 3.93 (d, 6H), 1.29 (t, 3H, J=7.2 Hz).

Example 32

1-Ethyl-3-(4-fluorophenyl)-6-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide. mp=260-4°C.; LCMS m/z=589 (M+1); ¹H NMR (DMSO) δ: 10.71 (s, 1H), 8.46 (d, 1H),J=5.2 Hz), 7.90, 7.94 (dd, 1H, J=2.3, 12.7 Hz), 7.53 (s, 1H), 7.40-7.47(m, 3H), 7.32-7.36 (m, 4H), 6.46 (d, 1H, J=5.2 Hz), 3.97 (q, 2H, J=7Hz), 3.94 (s, 6H), 2.47 (s, 3H), 1.25 (t, 3H, J=7.2 Hz).

Example 33

1-Ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid [4-(6,7-diethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide. mp=216-8°C.; LCMS m/z=603 (M+1); ¹H NMR (DMSO) δ: 11.03 (s, 1H), 8.89 (s, 1H),8.45 (d, 1H, J=5.2 Hz), 7.98, 8.02 (dd, 1H, J=2.2, 13 Hz), 7.50-7.54 (m,2H), 7.31-7.45 (m, 6H), 6.45 (d, 1H, J=5.2 Hz), 4.21 (m, 4H), 4.01 (q,2H, J=6.4 Hz), 1.42 (m, 6H), 1.29 (t, 3H, J=7.2 Hz).

Example 34

3-(4-Fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid [5-(6,7-dimethoxyquinolin-4-yloxy)-pyridin-2-yl]-amide wassynthesized using the method for example 31. mp=220-4° C.; LCMS m/z=572(M+1); ¹H NMR DMSO) δ: 11.40 (s, 1H), 8.72 (s, 1H), 8.49 (d, 1H, J=5.2Hz), 8.36 (d, 1H, J=6.5 Hz), 8.35 (s, 1H), 8.86, 7.84 (dd, 1H, J=3.0,9.3 Hz), 7.52 (s, 1H), 7.41-7.45 (m, 3H), 7.34-7.39 (m, 2H), 6.55 (d,1H, J=5.4 Hz), 4.78 (h, 1H, J=6.8 Hz), 3.94, 3.93 (d, 6H), 1.43 (d, 6H,J=6.9 Hz).

Example 35

1-Cyclopropylmethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid [5-(6,7-dimethoxyquinolin-4-yloxy)pyridin-2-yl]-amide wassynthesized using the method for example 31. LCMS m/z=584 (M+1); ¹H NMR(DMSO) δ: 11.43 (s, 1H), 8.97 (s, 1H), 8.74 (m, 1H), 8.44 (m, 2H), 7.96(m, 1H), 7.70 (s, 1H), 7.50 (s, 1H), 7.42-7.46 (m, 2H), 7.34-7.39 (m,2H), 6.91 (m, 1H), 4.0, 4.02 (ss, 6H), 3.88 (m, 2H), 1.21 (m, 1H), 0.55(m, 2H), 0.45 (m, 2H).

Example 36

3-(4-Fluorophenyl)-2,4-dioxo-1-pentyl-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide.mp=128-30° C.; LCMS m/z=617 (M+1); ¹H NMR (DMSO) δ: 11.0 (s, 1H), 8.85(s, 1H), 8.47 (d, 1H, J=4.7 Hz), 8.0 (d, 1H, J=12.6 Hz), 7.52-7.55 (m,2H), 7.33-7.45 (m, 6H), 6.46 (d, 1H, J=4.5 Hz), 3.95 (bm, 8H), 1.70(brm, 2H), 1.32 (bm, 4H), 0.89 (bm, 3H).

Example 37

3-(4-Fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid [4-(6,7-diethoxyquinolin-4-yloxy)-3-fluoro-phenyl]-amide.mp=128-130° C.; LCMS m/z=617 (M+1); ¹H NMR (DMSO) δ: 11.0 (s, 1H), 8.68(s, 1H), 8.45 (d, 1H, J=5 Hz), 7.99 (d, 1H, J=13 Hz), 7.50-7.54 (m, 2H),7.33-7.45 (m, 6H), 6.45 (d, 1H, J=5 Hz), 4.78 (m, 1H), 4.20 (m, 4H),1.42 (m, 12H).

Example 38

Step a. Meldrum acid (470 mg, 3.20 mmol) in triethylorthoformate (4 mL)and heated at 100° C. for 1.5 h. 3,5-Dimethoxyaniline (500 mg, 3.2 mmol)was added and heated and heated at 100° C. for 4 h. The reaction mixturewas cooled to rt and hexanes added and stirred. The yellow solid wascollected and dried to yield a yellow solid. LCMS m/z=308 (M+1); ¹H NMR(CDCl₃) a; 8.61 (d, 1H, J=14.0 Hz), 6.365 (m, 3H), 3.82 (s, 6H), 1.76(s, 6H).

Step b.5-[(3,5-Dimethoxyphenylamino)-methylene]-2,2-dimethyl[1,3]dioxane-4,6-dione(400 mg, 1.30 mmol) in diphenyl ether (5 mL) and heated at 200° C. for30 min. The reaction mixture was cooled to rt and hexane was added andstirred for 30 min. The brown solid was filtered and dried to yield5,7-dimethoxy-1H-quinolin-4-one LCMS m/z=206 (M+1).

Step c. 5,7-dimethoxy-1H-quinolin-4-one (300 mg, 1.4 mmol) in POCl₃ (5mL) was heated to reflux for 15 h. The reaction mixture was cooled to rtand poured into ice-water. The mixture was then basified to pH 7 withNaHCO₃ and stirred overnight. The solid was filtered and washed withwater and dried to give 4-chloro-5,7-dimethoxyquinoline. LCMS m/z=224(M+1); ¹H NMR (CDCl₃) δ: 8.56 (d, 1H, J=4.4 Hz), 7.23 (d, 1H, J=4.4 Hz),7.05 (s, 1H), 6.58 (s, 1H), 3.93 (s, 6H).

Step d. 4-Chloro-5,7-dimethoxyquinoline (100 mg, 0.40 mmol) andp-nitrophenol (124 mg, 0.89 mmol) in chlorobenzene (2 mL) was heated atreflux for 14 h. Then the reaction mixture was cooled to rt, filtered,and the residue washed with toluene. The solid was suspended in 10% NaOHsolution and stirred for 1 h at rt. The yellow solid was collected andwashed with EtOAc to give 5,7-dimethoxy-4-(4-nitrophenoxyl)quinoline.LCMS m/z=327 (M+1); ¹H NMR (CDCl₃) δ: 8.60 (d, 1H, J=6.0 Hz), 8.44 (d,2, J=8.8 Hz), 7.72 (s, 1H), 7.35 (d, 2H, J=8.4 Hz) 6.71 (s, 1H), 6.69(d, 2H, J=6.4 Hz), 4.08 (s, 3H), 3.97 (s, 3H).

Step e. A mixture of 5,7-dimethoxy-4-(4-nitrophenoxyl)quinoline (50 mg,0.15 mmol), Zn dust (100 mg, 1.50 mmol) and ammonium chloride (32 mg,0.60 mmol) in methanol (3 mL) was heated at reflux for 1 h. The mixturewas filtered through celite and washed with CHCl₃. The organic layer waswashed with 10% NaOH solution and brine, dried over Na₂SO₄, andconcentrated to afford 4-(5,7-dimethoxyquinolin-4-yloxy)phenylamine asan off white solid. LCMS m/z=298 (M+1); ¹H NMR (CDCl₃) δ: 8.44 (d, 1H,J=4.8 Hz), 7.00 (s, 1H), 6.83 (d, 2H, J=8.8 Hz), 6.65-6.63 (m, 3H), 6.32(d, 1H, J=4.8 Hz), 5.11 (br s, 2H), 3.89 (s, 3H), 3.86 (s, 3H).3-(4-Fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid [4-(5,7-dimethoxyquinolin-4-yloxy)phenyl]-amide. mp=122-4° C.; LCMSm/z=571 (M+1); ¹H NMR (DMSO) δ: 10.87 (s, 1H), 8.65 (s, 1H), 8.53 (d,1H, J=5.3 Hz), 7.73 (d, 2H, J=9 Hz), 7.42 (m, 2H), 7.35 (m, 2H), 7.07(d, 2H, J=9 Hz), 6.99 (d, 1H, J=2 Hz), 6.63 (d, 1H, J=2 Hz), 6.50 (d,1H, J=5 Hz), 4.78 (q, 1H, J=7 Hz), 3.90 (s, 3H), 3.80 (s, 3H), 1.42 (d,6H, J=7 Hz).

Example 39

1-Ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid [4-(5,7-dimethoxyquinolin-4-yloxy)-phenyl]-amide was synthesizedusing 4-(5,7-dimethoxyquinolin-4-yloxy)phenylamine and3-(4-fluorophenyl)-1-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid by the method for example 38. mp=128-9° C.; LCMS m/z=557 (M+1); ¹HNMR (DMSO) δ: 10.87 (s, 1H), 8.85 (s, 1H), 8.52 (m, 1H), 7.72 (m, 2H),7.33-7.41 (m, 4H), 7.07 (m, 2H), 6.99 (m, 1H), 6.63 (m, 1H), 6.49 (m,1H), 4.01 (m, 2H), 3.90 (s, 3H), 3.81 (s, 3H), 1.28 (m, 3H).

Example 40

Step a. 4-(7-Benzyloxy-6-methoxyquinolin-4-yloxy)-3-fluorophenylamine.Sodium hydride (60% disp. in mineral oil, 0.534 g, 13.3 mmol) was addedto 4-amino-2-fluorophenol in dry N,N-dimethylformamide (10.3 mL) at rtand stirred for 30 min under an atmosphere of nitrogen. Then solid7-benzyloxy-4-chloro-6-methoxyquinoline (2.00 g, 6.67 mmol) was addedand the reaction stirred at 100° C. for 30 h. The mixture wasconcentrated, dissolved in EtOAc (about 75 mL), and washed with 1NNa₂CO₃, water and brine, then dried over MgSO₄. The product waschromatographed on silica gel (5% MeOH/DCM) to give a brown solid 1.9 g(73%). LCMS m/z=391 (M+1); ¹H NMR (DMSO) δ: 8.43 (s, 1H), 7.36-7.52 (m,7H), 7.07 (m, 1H), 6.38-6.56 (m, 3H), 5.50 (m, 2H), 5.3 (s, 2H), 3.95(s, 3H).

Step b.1-Ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid [4-(7-benzyloxy-6-methoxyquinolin-4-yloxy)-3-fluorophenyl]-amidewas synthesized using4-(7-benzyloxy-6-methoxyquinolin-4-yloxy)-3-fluorophenylamine and3-(4-fluorophenyl)-1-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid by the method for example 1. mp=142-4° C.; LCMS m/z=651 (M+1); ¹HNMR (DMSO) δ: 11.0 (s, 1H), 8.89 (s, 1H), 8.47 (d, 1H, J=5.3 Hz), 7.98,8.02 (dd, 1H, J=2.3, 13 Hz), 7.50-7.54 (m, 5H), 7.41-7.46 (m, 5H),7.33-7.38 (m, 3H), 6.48 (d, 1H, J=5 Hz), 5.31 (s, 2H), 4.90 (q, 2H, J=7Hz), 3.95 (s, 3H), 1.29 (t, 3H, J=7 Hz).

Example 41

3-(4-Fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid [4-(7-benzyloxy-6-methoxyquinolin-4-yloxy)-3-fluorophenyl]-amidewas synthesized using the method for example 40 and3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid. mp=184-6° C.; LCMS m/z=665 (M+1); ¹H NMR (DMSO) δ: 11.0 (s, 1H),8.6 (s, 1H), 8.46 (d, 1H, J=5.3 Hz), 8.0, 8.02 (dd, 1H, J=2.4, 12.6 Hz),7.48-7.54 (m, 5H), 7.41-7.46 (m, 5H), 7.33-7.38 (m, 3H), 6.47 (d, 1H,J=5 Hz), 5.31 (s, 2H), 6.78 (m, 1H), 3.95 (s, 3H), 1.43 (d, 6H, J=5.5Hz).

Example 42

1-Ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid [3-fluoro-4-(7-hydroxy-6-methoxyquinolin-4-yloxy)phenyl]-amide.Example 40 (0.50 g, 0.77 mmol) and 20% Pd(OH)2/C, 50% wet (10:40:50,palladium hydroxide:carbon black:Water, 0.1 g, 0.07 mmol) inN,N-dimethylformamide (10 mL) was hydrogenated on a Parr apparatus underan atmosphere of hydrogen 40 psi for 12 h. The solvent was removed andthe product was triturated with ether to give 42-mg (97%) as a whilesolid. mp>200° C. dec; LCMS m/z=561 (M+1); ¹H NMR (DMSO) δ: 11.75 (bs,1H), 11.11 (s, 1H), 8.89 (s, 1H), 8.73 (d, 1H, J=6.5 Hz), 8.07, 8.11(dd, 1H, J=2.3, 12.5 Hz), 7.72 (s, 1H), 7.54-7.64 (m, 3H), 7.41-7.45 (m,2H), 7.34-7.39 (m, 2H), 6.90 (d, 1H, J=6.5 Hz), 4.0-4.05 (s, m, 5H),1.30 (t, 3H, J=7.2 Hz).

Example 43

1-Ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid{3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)quinolin-4-yloxy]phenyl}-amide.Example 42 (0.100 g, 0.178 mmol), methanesulfonic acid3-morpholin-4-yl-propyl ester (0.0438 g, 0.196 mmol) and cesiumcarbonate (0.116 g, 0.357 mmol) in N,N-dimethylformamide (2 mL) washeated at 65° C. for 8 h. The mixture was diluted with EtOAc andextracted with 1N Na₂CO₃, water and brine solutions then dried overMgSO₄. The solid was triturated with ether, then the ether decanted andthe product precipitated with hexanes to give a white solid. mp=92-5°C.; LCMS m/z=688 (M+1); ¹H NMR (DMSO) δ: 11.04 (s, 1H), 8.89 (s, 1H),8.46 (d, 1H, J=5.3 Hz), 7.98, 8.02 (dd, 1H, J=2.4, 13 Hz), 7.51-7.55 (m,2H), 7.33-7.46 (m, 6H), 6.46 (d, 1H, J=5.4 Hz, 4.20 (t, 2H, J=6.4 Hz),4.01 (q, 2H, J=7.4 Hz), 3.94 (s, 3H), 3.58 (t, 4H, J=4.8 Hz), 2.45 (m,2H), 2.39 (b, 4H), 1.98 (m, 2H), 1.29 (t, 3H, J=7.2 Hz).

Example 44

1-Ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid{3-fluoro-4-[6-methoxy-7-(2-methoxyethoxyl)quinolin-4-yloxy]-phenyl}-amide.Example 44 was synthesized by the procedure for example 43 using example42 and 1-bromo-2-methoxyethane. mp=178-80° C.; LCMS m/z=619 (M+1); ¹HNMR (DMSO) δ: 11.00 (s, 1H), 8.89 (s, 1H), 8.46 (d, 1H, J=5 Hz), 7.98,8.00 (dd, 1H, J=2, 13 Hz), 7.52-7.55 (m, 2H), 7.42-7.46 (m, 4H),7.33-7.38 (m, 2H), 6.47 (d, 1H, J=5.4 Hz), 4.28 (m, 2H), 4.01 (q, 2H,J=7.1 Hz), 3.95 (s, 3H), 3.76-(m, 2H), 3.34 (s, 3H), 1.29 (t, 3H, J=7.1Hz).

Example 45

1-Ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid{3-fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]phenyl}-amide.Example 45 was synthesized by the procedure for example 43 using example42 and 4-(2-chloroethyl)morpholine hydrochloride. mp=222-224° C.; LCMSm/z=674 (M+1); ¹H NMR (DMSO) δ: 11.0 (s, 1H), 8.89 (s, 1H), 8.47 (d, 1H,J=5.4 Hz), 7.98, 8.01 (dd, 1H, J=2.4, 12.6 Hz), 7.52-7.55 (m, 2H),7.41-7.46 (m, 4H), 7.33-7.38 (m, 2H), 6.46 (d, 1H, J=5.4 Hz), 4.27 (t,2H, J=6 Hz), 4.02 (q, 2H, J=7.4 Hz), 3.94 (s, 3H), 3.59 (t, 4H, J=4.6Hz), 2.79 (t, 2H, J=5.8 Hz), 2.53 (m, 4H), 1.29 (t, 3H, J=7.4 Hz).

Example 46

3-(4-Fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid [3-fluoro-4-(7-hydroxy-6-methoxyquinolin-4-yloxy)-phenyl]-amide.Example 46 was synthesized using example 41 and the procedure forexample 42. mp=205-7° C.; LCMS m/z=575 (M+1); ¹H NMR (DMSO) δ: 11.7 (s,1H), 11.1 (s, 1H), 8.73 (d, 1H, J=7 Hz), 8.68 (s, 1H), 8.07, 8.11 (dd,1H, J=2.4, 12.7 Hz), 7.72 (s, 1H), 7.54-7.64 (m, 3H), 7.34-7.45 (m, 4H),6.89 (d, 1H, J=6.5 Hz), 4.78 (m, 1H), 4.0 (s, 3H), 1.42 (d, 6H, J=7 Hz).

Example 47

3-(4-Fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid{3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]phenyl}-amide.Example 47 was synthesized by the procedure for example 43 using example46. mp=160-162° C.; LCMS m/z=701 (M+1); ¹H NMR (DMSO) δ: 11.0 (s, 1H),8.68 (s, 1H), 8.47 (d, 1H, 5.3 Hz), 7.99, 8.02 (dd, 1H, J=2.3, 13 Hz),7.5′-7.55 (m, 2H), 7.33-7.45 (m, 6H), 6.46 (d, 1, J=5.3 Hz), 4.78 (m,1H), 4.2 (t, 2H, J=6.8 Hz), 3.94 (s, 3H), 3.58 (m, 4H), 2.45 (m, 2H),2.38 (m, 4H), 1.97 (m, 2H), 1.42 (d, 6H, J=7 Hz).

Example 48

1-Ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluoro-phenyl]-methyl-amide.Example 1 (0.050 g, 0.087 mmol) in N,N-dimethylformamide (2 mL) at 5° C.(ice bath) was added sodium hydride, 60% disp. in mineral oil (0.0052 g,0.13 mmol). The mixture was stirred 0.5 h, and then methyl iodide(0.0081 mL, 0.13 mmol) was added. After 2 h, EtOAc was added, washedwith 1N Na₂CO₃, water and brine. The product was purified by prep LC/MS.The fractions were combined and concentrated and the solid wascrystallized with EtOAc, ether and hexanes to give a white solid as theTFA salt. mp=112-5° C.; LCMS m/z=589 (M+1); ¹H NMR (DMSO) δ: 8.66 (d,1H, J=5.9 Hz), 8.23 (s, 1H), 7.65 (s, 1H), 7.51-7.60 (m, 3H), 7.25-7.30(m, 3H), 7.13-7.16 (m, 2H), 6.6 (d, 1H, J=5.8 Hz), 4.01 (d, 6H), 3.8 (q,2H, J=7 Hz), 3.35 (s, 3H), 1.22 (t, 3H, J=7 Hz).

Example 49

3-(4-Fluorophenyl)-1-(2-hydroxyethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide. Example10 (0.06 g, 0.09 mmol) and palladium hydroxide (20%) on carbon (0.016 g,0.024 mmol) in ethyl acetate (7 mL) and MeOH (3 mL) was added 2 drops of5N HCl. The mixture was hydrogenated under an atmosphere of hydrogen ona Parr apparatus at 40 psi for 2 h. The mixture was diluted with EtOAcand washed with 1N Na₂CO₃, and brine, then dried over MgSO₄. Thesolution was concentrated and the product was triturated withether-hexanes and the solid collected and dried at 60° C. under vacuum.mp=166-8° C.; LCMS m/z=591 (M+1); ¹H NMR (DMSO) δ: 11.00 (s, 1H), 8.75(s, 1H), 8.47 (d, 1H, J=5.4 Hz), 7.98, 8.01 (dd, 1H, J=2.2, 13 Hz),7.52-7.55 (m, 2H), 7.34-7.46 (m, 6H), 6.47 (d, 1H, J=5 Hz), 5.03 (t, 1H,J=5.4 Hz), 4.05 (m, 2H), 3.94 (d, 6H), 3.67 (m, 2H).

Example 50

3-(4-Fluorophenyl)-1-(3-hydroxypropyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide. Example50 was synthesized using example 13 by the procedure for example 49.mp=124-6° C.; LCMS m/z=605 (M+1); 1H NMR (DMSO) δ: 11.00 (s, 1H), 8.82(s, 1H), 8.47 (d, 1H, J=5.4 Hz), 7.98, 8.01 (dd, 1H, J=2.5, 13 Hz),7.52-7.55 (m, 2H), 7.33-7.46 (m, 6H), 6.47 (d, 1H, J=6 Hz), 4.63 (t, 1H,J=5 Hz), 4.05 (t, 2H, J=7 Hz), 3.94 (s, s, 6H), 3.50 (q, 2H, J=5 Hz),1.85 (p, 2H, J=6.2 Hz).

Example 51

3-(4-Fluorophenyl)-1-(3-hydroxypropyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-2-fluoro-phenyl]-amide. Example51 was synthesized using example 22 by the procedure for example 49.mp=220-4° C.; LCMS m/z=605 (M+1); ¹H NMR (DMSO) δ: 11.16 (s, 1H), 8.83(s, 1H), 8.45-8.50 (m, 2H), 7.47 (s, 1H), 7.33-7.44 (m, 6H), 7.16 (d,1H, J=9 Hz), 6.58 (d, 1H, J=5 Hz), 4.63 (t, 1H, J=4.9 Hz), 4.04 (t, 2H,J=7 Hz), 3.94 (s, 3H), 3.92 (s, 3H), 3.50 (q, 2H, J=5.4 Hz), 1.84 (q,2H, J=7 Hz).

Example 52

3-(4-Fluorophenyl)-1-(3-hydroxypropyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid [4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-amide. Example 52 wassynthesized using example 21 by the procedure for example 49. mp=123-6°C.; LCMS m/z=587 (M+1); ¹H NMR (DMSO) δ: 10.93 (s, 1H), 8.79 (s, 1H),8.47 (d, 1H, J=5 Hz), 7.8)d, 2H, J=9 Hz), 7.50 (s, 1H), 7.33-7.44 (m,5H), 7.25 (d, 2H, J=9 Hz), 6.47 (d, 1H, j=5.6 Hz), 4.63 (t, 1H, J=5 Hz),4.04 (t, 2H, J=7 Hz), 3.94 (s, 3H), 3.92 (s, 3H), 3.50 (q, 2H, J=5 Hz).

Example 53

3-(4-Fluorophenyl)-1-(2-hydroxyethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid [4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-amide. Example 53 wassynthesized using example 19 by the procedure for example 49. mp=153-4°C.; LCMS m/z=573 (M+1); 1H NMR (DMSO) δ: 10.91 (s, 1H), 8.74 (s, 1H),8.47 (d, 1H, J=5.8 Hz), 7.80 (d, 2H, J=9 Hz), 7.49 (s, 1H), 7.34-7.43(m, 5H), 7.26 (d, 2H, J=9 Hz), 6.48 (d, 1H, J=5.4 Hz), 5.02 (t, 1H,J=5.2 Hz), 4.03 (m, 2H), 3.94 (s, 3H), 3.92 (s, 3H), 3.67 (m, 2H).

Example 54

1-((S)-2,3-Dihydroxypropyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide.1-((S)-2,2-Dimethyl-1,3-dioxolan-4-ylmethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (0.0446 g, 0.122 mmol) andN,N,N′,N-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (0.0466 g, 0.122 mmol) in N,N-dimethylformamide(2.00 mL) was added N,N-diisopropylethylamine (0.0388 mL, 0.223 mmol)and stirred at rt for 15 min.4-(6,7-Dimethoxyquinolin-4-yloxy)-3-fluorophenylamine (0.035 g, 0.11mmol) was added and stirred overnight. The solution was diluted withEtOAc, washed with 1N Na₂CO₃, water and brine then dried over MgSO4 andconcentrated. MeOH was added (1 mL) and a solid separated. This materialwas dissolved in 4 M of hydrogen chloride in 1,4-dioxane (2 mL, 8 mmol),stirred for 2 h and then concentrated. To this product was added MeOHand the precipitate collected to give a white solid. mp=165-6° C.; LCMSm/z=621 (M+1); ¹H NMR (DMSO) δ: 11.0 (s, 1H), 8.72 (s, 1H), 8.48 9d, 1H,J=5.4 Hz), 8.01, 7.98 (dd, 1H, J=2.4, 13.5 Hz), 7.52-7.55 (j, 1H),7.34-7.46 (m, 6H), 6.47 (d, 1H, J=5.4 Hz), 6.17 (d, 1H, J=5 Hz), 4.78(t, 1H, J=5.7 Hz), 4.22 (d, 1H, J=10 Hz), 3.94 (d, 6H), 3.75-3.78 (m,2H), 3.3 (m, 2H).

Example 55

3-(4-Fluorophenyl)-1-(4-hydroxybutyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide. LCMSm/z=619 (M+1); ¹H NMR (DMSO) δ: 11.04 (s, 1H), 8.86 (s, 1H), 8.47 (d,1H, J=5 Hz), 8.00 (d, 1H, J=12 Hz), 7.52-7.55 (m, 2H), 7.33-7.46 (m,6H), 6.47 (d, 1H, J=5 Hz), 4.48 (t, 1H, J=4.5 Hz), 3.99 (m, 2H), 3.94(d, 6H), 3.42 (m, 2H), 1.73 (m, 2H), 1.48 (m, 2H).

Example 56

4-(2-fluoro-4-methylaminophenoxy)-7-methoxyquinoline-6-carbonitrile wassynthesized by the method described for4-(5,7-dimethoxyquinolin-4-yloxy)phenylamine example 38 starting with4-amino-2-methoxybenzonitrile; LCMS m/z=309 (M+1); ¹H NMR (DMSO-d6) δ:8.73 (s, 1H), 8.71 (d, 1H, J=5.2 Hz), 7.58 (s, 1H), 6.95 (d, 2H, J=8.8Hz), 6.67 (d, 2H, J=8.4 Hz), 6.48 (d, 1H, J=5.6 Hz), 5.20 (br s, NH,2H), 4.06 (s, 3H).3-(4-Fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid [4-(6-cyano-7-methoxy-quinolin-4-yloxy)-phenyl]-amide.N,N,N′,N-Tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (0.066 g, 0.17 mmol) and3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (0.062 g, 0.21 mmol) in N,N-dimethylformamide (2 mL, 20 mmol) wasadded N,N-diisopropylethylamine (0.055 mL, 0.32 mmol). After 15 minstirring at rt 4-(4-aminophenoxy)-7-methoxyquinoline-6-carbonitrile(0.05 g, 0.2 mmol) was added. The reaction was stirred at rt overnight,diluted with EtOAc, washed with 1N Na₂CO₃, water and brine solutionsthen dried over MgSO₄. The product was recrystallized from MeOH thendried overnight at 65° C. under vacuum to give a tan solid. mp=202-3°C.; LCMS m/z=566 (M+1); ¹H NMR (DMSO) δ: 10.96 (s, 1H), 8.77 (s, 1H),8.74 (d, 1H, J=5 Hz), 8.67 (s, 1H), 7.83 (d, 2H, J=7.3 Hz), 7.61 (s,1H), 7.42-7.45 (m, 2H), 7.30-7.38 (m, 5H), 6.56 (d, 1H, J=5.5 Hz), 4.78(q, 1H, J=7 Hz), 4.07 (s, 3H), 1.43 (d, 6H, J=7 Hz).

Example 57

Step a.(4-Bromo-2-fluoro-phenyl)-(6,7-dimethoxy-quinolin-4-yl)-methanol. Asolution of 4-bromo-6,7-dimethoxyquinoline (0.5 g, 1.8 mmol) intetrahydrofuran (6 mL) was cooled at −78° C. n-Butyllithium (0.89 mL,2.23 mmol, 2.5 M solution in hexane) was added dropwise under an argonatmosphere and further stirred at −78° C. for 1 h.4-Bromo-2-fluoro-benzaldehyde (0.45, 2.2 mmol) in 3 mL oftetrahydrofuran was added dropwise. The reaction mixture was stirred at−78° C. for 1 h and slowly warmed to 0° C. for 1.5 h. The reaction wasquenched with satd. NH₄Cl solution and extracted three times with CH₂Cl₂and the combined organics were washed with brine, dried (Na₂SO₄),filtered, and evaporated to yield a crude product. The crude product waspurified by silica gel column chromatography to produce(4-bromo-2-fluoro-phenyl)-(6,7-dimethoxy-quinolin-4-yl)-methanol (0.45g, 62%) as a yellow solid. MS m/z=393 (M+1).

Step b.(4-Amino-2-fluoro-phenyl)-(6,7-dimethoxy-quinolin-4-yl)-methanol. Amixture of4-bromo-2-fluoro-phenyl)-(6,7-dimethoxy-quinolin-4-yl)-methanol (0.72 g,1.8 mmol), bis(dibenzylideneacetone)palladium(0) (0.19 g, 0.33 mmol),tri-t-butylphosphine (0.54 mL, 10% solution), lithiumhexamethyldisilazide (6.24 mL, 3.46 mmol, 1 M solution in THF) andtoluene (5 mL) was charged in a pressure reaction vessel with a screwcap. The mixture was heated at 80° C. for 3 h under an argon atmosphereand quenched with MeOH. The crude product was purified by Gilson prep.HPLC to produce4-amino-2-fluoro-phenyl)-(6,7-dimethoxy-quinolin-4-yl)-methanol (0.4 g,66%). MS m/z=329 (M+1).

Step c.3-(4-fluoro-phenyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid{4-[(6,7-dimethoxy-quinolin-4-yl)-hydroxy-methyl]-3-fluoro-phenyl}-amide.To a well stirred mixture of3-(4-fluorophenyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (0.058 g, 0.252 mmol) andN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)-uroniumhexafluorophosphate (0.096 g, 0.25 mmol) in N, N-dimethylformamide (2mL) was added N, N-diisopropylethylamine (0.26 mL, 1.5 mmol). Afterstirring for 10 min,4-amino-2-fluoro-phenyl)-(6,7-dimethoxyquinolin-4-yl)-methanol (0.072 g,0.21 mmol) was added. The reaction mixture was stirred at rt overnightand purified by Gilson prep. HPLC to produce (0.02 g, 17%) as a solid.mp 164-166°; LCMS m/z=546 (M+1). ¹H NMR (DMSO-d₆) δ:10.92 (s, 1H), 8.82(s, 1H), 8.68 (d, 1H, J=4.6 Hz), 7.73 (dd, 1H. J=1.9 Hz, J=12.8 Hz),7.52 (d, 1H, J=4.56 Hz), 7.31-7.39 (m, 6H), 7.25-7.27 (m, 2H), 6.5 (d,1H, J=4.5 Hz), 6.28 (d, 1H, J=4.6 Hz), 3.88 (s, 3H), 3.81 (s, 3H), 3.50(s, 3H).

Example 58

3-(4-fluoro-phenyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-ylmethyl)-3-fluoro-phenyl]-amide. Amixture of example 57 (0.08 g, 0.13 mmol) and zinc (1.4 g, 21.5 mmol) informic acid (5 mL) was heated at 60° C. for 5 h. The reaction mixturewas diluted with CH₂Cl₂ and filtered over a celite and washed withCH₂Cl₂. The filtrate was evaporated and purified by Gilson prep. HPLC togive a white solid (33 mg, 42%), mp 293-295° C.; MS m/z=559 (M+H). ¹HNMR (DMSO-d₆) δ:10.92 (s, 1H), 8.84 (s, 1H), 8.55 (d, 1H, J=4.5 Hz),7.78 (dd, 1H, J=1.80 Hz, J=12.4 Hz), 7.32-7.39 (m, 6H), 7.21-7.29 (m,2H), 7.01 (d, 1H, J=4.48 Hz), 4.38 (s, 2H), 3.91 (s, 3H), 3.90 (s, 3H),3.51 (s, 3H).

Example 59

Step a. 4-(2-Bromo-4-nitro-phenoxy)-6,7-dimethoxy-quinoline. A mixtureof 4-chloro-6,7-dimethoxyquinoline (0.82 g, 3.67 mmol),2-bromo-4-nitrophenol (0.80 g, 3.67 mmol) and 4-dimethylaminopyridine(0.067 g, 0.549 mmol) in chlorobenzene (8 mL) was heated at 140° C. for2 days under an argon atmosphere. The crude product was purified bysilica gel column chromatography followed by crystallization from amixture of CH₂Cl₂, MeOH, ether, and hexane to produce4-(2-bromo-4-nitrophenoxy)-6,7-dimethoxyquinoline (0.74 g, 50%), LCMSm/z=406 (M+1).

Step b. 4-(2-Cyclopropyl-4-nitro-phenoxy)-6,7-dimethoxy-quinoline. Amixture of 4-(2-bromo-4-nitro-phenoxy)-6,7-dimethoxy-quinoline (0.74 g,1.8 mmol), potassium cyclopropyltrifluoroborate (0.49 g, 3.39 mmol),palladium acetate (0.07 g, 0.31 mmol),butyl-ditricyclo[3.3.1.1(3,7)]decan-1-yl-phosphane (0.12 g, 0.34 mmol),and cesium carbonate (3.07 g, 9.44 mmol) in a mixture of toluene (24 mL)and water (3.4 mL) was heated at 85° C. for overnight. The reactionmixture was diluted with CH₂Cl₂ and filtered over a pad of celite,washed with CH₂Cl₂. The filtrate was evaporated and purified by Gilsonprep. HPLC to produce4-(2-cyclopropyl-4-nitro-phenoxy)-6,7-dimethoxyquinoline (0.44 g, 65%).LCMS m/z=367 (M+1).

Step c. 3-Cyclopropyl-4-(6,7-dimethoxy-quinolin-4-yloxy)-phenylamine. Amixture of 4-(2-cyclopropyl-4-nitro-phenoxy)-6,7-dimethoxy-quinoline(0.30 g, 0.82 mmol) and tin(II) chloride dihydrate (0.92 g, 4.09 mmol)in a mixture of ethanol (10 mL) and ethyl acetate (3 mL) was refluxedfor 2 h. The reaction mixture was evaporated and partitioned betweenCH₂Cl₂ and satd. NaHCO₃ solution. The heterogeneous mixture was filteredover celite, washed with CH₂Cl₂ and the filtrate was separated into twophases. The aqueous phase was extracted two times with CH₂Cl₂ and thecombined organics was washed with brine, dried (Na₂SO₄), filtered, andevaporated to yield a crude product. The crude product was purified bysilica gel column chromatography to produce3-cyclopropyl-4-(6,7-dimethoxy-quinolin-4-yloxy)-phenylamine (0.22 g,80%), MS m/z=337 (M+1). ¹H NMR (CDCl₃) δ: 8.54 (d, 1H, J=5.2 Hz), 8.1(dd, 1H, J=2.73 Hz, J=8.9 Hz), 7.90 (d, 1H, J=2.72 Hz), 7.52 (s, 1H),7.46 (s, 1H), 7.16 (d, 1H, J=8.85 Hz), 6.43 (d, 1H, J=5.2 Hz), 4.06 (s,3H), 4.04 (s, 3H), 2.04-2.14 (m, 1H), 1.59 (brs, 2H), 0.95-1.04 (m, 2H),0.78-0.86 (m, 2H).

Step d.

1-Ethyl-3-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid [3-cyclopropyl-4-(6,7-dimethoxy-quinolin-4-yloxy)-phenyl]-amide wassynthesized from3-cyclopropyl-4-(6,7-dimethoxyquinolin-4-yloxy)phenylamine (0.06 g, 0.20mmol) and3-(4-fluoro-phenyl)-1-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (0.06 g, 0.21 mmol) in an analogous manner to Example 1. mp183-185° C.; LCMS m/z=597 (M+1). ¹H NMR (DMSO-d₆) δ: 10.84 (s, 1H), 8.86(s, 1H), 8.44 (d, 1H, J=5.2 Hz), 7.71 (d d, 1H, J=2.53 Hz, J=8.73 Hz),7.58 (s 1H), 7.31-7.46 (m, 5H), 7.27 (d, 1H, J=2.53 Hz), 7.17 (d, 1H,J=8.73 Hz), 6.33 (d, 1H, J=5.2 Hz), 4.00 (q, 2H, J=7.04 Hz), 3.94 (s,6H), 1.77-1.87 (m, 1H), 1.29 (t, 3H, J=7.04 Hz), 0.72-0.82 (m, 2H),0.62-0.71 (m, 2H).

Example 60

3-(4-Fluoro-phenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid [3-cyclopropyl-4-(6,7-dimethoxy-quinolin-4-yloxy)-phenyl]-amide.This compound was synthesized from3-cyclopropyl-4-(6,7-dimethoxyquinolin-4-yloxy)phenylamine (0.06 g, 0.20mmol) and3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (0.063 g, 0.21 mmol) in an analogous manner to Example 59. mp172-174° C.; LCMS m/z=611 (M+1). ¹H NMR (DMSO-d₆) δ: 10.86 (s, 1H), 8.67(s, 1H), 8.44 (d, 1H, J=5.24 Hz), 7.65 (dd, 1H, J=2.52 Hz, J=7.65 Hz),7.58 (s, 1H), 7.31-7.48 (m, 6H), 7.16 (d, 1H, J=8.73 Hz), 6.34 (d, 1H,J=5.20 Hz), 4.70-4.85 (m, 1H), 3.94 (s, 6H), 1.78-1.88 (m, 1H),0.73-0.82 (m, 2H), 0.62-0.69 (m, 2H).

The following examples were synthesized using the procedures for Example1.

Example 61

3-(4-Fluoro-phenyl)-2,4-dioxo-1-prop-2-ynyl-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide. mp155-157° C.; LCMS m/z=585 (M+1); ¹H NMR (DMSO) δ: 10.97 (s, 1H), 8.95(s, 1H), 8.48 (d, 1H, J=5.5 Hz), 8.01 (dd, 1H, J=2.5 Hz, J=13 Hz), 7.56(bd, 1H, J=9.0 Hz), 7.53 (s, 1H), 7.47-7.42 (m, 3H), 7.41 (s, 1H),7.40-7.32 (m, 2H), 6.48 (d, 1H, J=5.0 Hz), 4.85 (d, 2H, J=2.5 Hz), 3.95(s, 3H), 3.94 (s, 3H), 2.69 (s, 1H).

Example 62

3-(4-Fluoro-phenyl)-1-(2-imidazol-1-yl-ethyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide. mp218-221° C.; LCMS m/z=641 (M+1); ¹H NMR (DMSO) δ: 11.05 (s, 1H), 9.20(s, 1H), 8.77 (s, 1H), 8.75 (m, 1H), 8.06 (dd, 1H, J=2.5 Hz, J=13 Hz),7.85 (t, 1H, J=1.7 Hz), 7.71 (t, 1H, J=1.7 Hz), 7.68 (s, 1H), 7.62 (dd,1H, J=1.7 Hz, J=9.0 Hz), 7.57 (s, 1H), 7.55 (t, 1H, J=9.0 Hz), 7.39 (s,2H), 7.27 (s, 2H), 6.84 (m, 1H), 4.59 (t, 2H, J=6.5 Hz), 4.45 (t, 2H,J=6.5 Hz), 4.02 (s, 3H), 4.01 (s, 3H).

Example 63

3-(4-Fluoro-phenyl)-2,4-dioxo-1-(2-pyrazol-1-yl-ethyl)-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide. mp149-151° C.; LCMS m/z=641 (M+1); ¹H NMR (DMSO) δ: 10.92 (s, 1H), 8.49(d, 1H, J=6.6 Hz), 8.36 (s, 1H), 7.97 (dd, 1H, J=2.5 Hz, J=12.5 Hz),7.81 (d, 1H, J=2.0 Hz), 7.54-7.50 (m, 3H), 7.46-7.34 (m, 6H), 6.48 (d,1H, J=4.8 Hz), 6.27 (t, 1H, J=2.0 Hz), 4.48 (t, 2H, J=5.7 Hz), 4.38 (t,2H, J=5.4 Hz), 3.95 (s, 3H), 3.94 (s, 3H).

Example 64

3-(4-Fluoro-phenyl)-2,4-dioxo-1-phenethyl-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide. mp168-170° C.; LCMS m/z=651 (M+1); ¹H NMR (DMSO) δ: 11.00 (s, 1H), 8.79(s, 1H), 8.48 (d, 1H, J=4.8 Hz), 7.99 (dd, 1H, J=2.5 Hz, J=12.5 Hz),7.56 (bd, 1H, J=9.0 Hz), 7.52 (s, 1H), 7.47-7.23 (m, 11H), 6.48 (d, 1H,J=5.6 Hz), 4.20 (t, 2H, J=6.8 Hz), 3.95 (s, 3H), 3.94 (s, 3H), 3.02 (t,2H, J=6.9 Hz).

Example 65

1-[2-(1,3-Dioxolan-2-yl-ethyl)]-3-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide. mp138-140° C.; LCMS m/z=647 (M+1); ¹H NMR (DMSO) δ: 11.01 (s, 1H), 8.82(s, 1H), 8.48 (d, 1H, J=5.4 Hz), 8.00 (dd, 1H, J=2.3 Hz, J=12.5 Hz),7.55 (bd, 1H, J=9.7 Hz), 7.54 (s, 1H), 7.49-7.34 (m, 6H), 6.47 (d, 1H,J=5.3 Hz), 4.93 (t, 1H, J=4.2 Hz), 4.10 (t, 2H, J=6.9 Hz), 3.95 (s, 3H),3.94 (s, 3H), 3.94-3.90 (m, 2H), 3.81-3.77 (m, 2H), 2.05 (q, 2H, J=4.5Hz).

Example 66

1-Diethylcarbamoylmethyl-3-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide. mp147-149° C.; LCMS m/z=660 (M+1); ¹H NMR (DMSO) δ: 10.98 (s, 1H), 8.86(s, 1H), 8.48 (d, 1H, J=4.5 Hz), 8.00 (dd, 1H, J=3.1 Hz, J=12.5 Hz),7.56 (bd, 1H, J=9.3 Hz), 7.53 (s, 1H), 7.47-7.34 (m, 6H), 6.48 (d, 1H,J=4.6 Hz), 4.96 (s, 2H), 3.95 (s, 3H), 3.94 (s, 3H), 3.39-3.28 (m, 4H),1.18 (t, 3H, J=7.0 Hz), 1.05 (t, 3H, J=7.1 Hz).

Example 67

3-(4-Fluoro-phenyl)-1-(2-morpholin-4-yl-2-oxo-ethyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide. mp159-161° C.; LCMS m/z=674 (M+1); ¹H NMR (DMSO) δ: 10.97 (s, 1H), 8.82(s, 1H), 8.49 (d, 1H, J=5.3 Hz), 8.00 (dd, 1H, J=2.6 Hz, J=12.6 Hz),7.56 (bd, 1H, J=9.5 Hz), 7.53 (s, 1H), 7.48-7.34 (m, 6H), 6.49 (d, 1H,J=5.0 Hz), 5.00 (s, 2H), 3.95 (s, 3H), 3.94 (s, 3H), 3.65 (t, 2H, J=4.4Hz), 3.60 (t, 2H, J=4.4 Hz), 3.52-3.46 (m, 4H).

Example 68

3-(4-Fluoro-phenyl)-2,4-dioxo-1-[2-(2-oxo-pyrrolidin-1-yl)-ethyl]-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide. mp157-159° C.; LCMS m/z=658 (M+1); ¹H NMR (DMSO) δ: 10.97 (s, 1H), 8.80(s, 1H), 8.48 (d, 1H, J=5.3 Hz), 8.00 (dd, 1H, J=2.6 Hz, J=12.6 Hz),7.55 (bd, 1H, J=9.5 Hz), 7.53 (s, 1H), 7.47-7.36 (m, 6H), 6.48 (d, 1H,J=5.0 Hz), 4.16 (t, 2H, J=4.6 Hz), 3.95 (s, 3H), 3.94 (s, 3H), 3.54-3.49(m, 4H), 2.12 (t, 2H, J=7.8 Hz), 1.93 (p, 2H, J=8.2 Hz).

Example 69

1-(2-Fluoro-ethyl)-3-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide. mp138-140° C.; LCMS m/z=593 (M+1); ¹H NMR (DMSO) δ: 11.00 (s, 1H), 8.82(s, 1H), 8.48 (d, 1H, J=5.2 Hz), 8.01 (dd, 1H, J=2.4 Hz, J=13 Hz), 7.55(bd, 1H, J=8.9 Hz), 7.52 (s, 1H), 7.48-7.33 (m, 6H), 6.48 (d, 1H, J=5.1Hz), 4.73 (dt, 2H, J=4.2 Hz, J=42 Hz), 4.36 (dt, 2H, J=4.2 Hz, J=28 Hz),3.95 (s, 3H), 3.94 (s, 3H).

Example 70

[5-[4-(6,7-Dimethoxy-quinolin-4-yloxy)-3-fluoro-phenylcarbamoyl]-3-(4-fluoro-phenyl)-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl]-aceticacid tert-butyl ester. mp 138-143° C.; LCMS m/z=661 (M+1); ¹H NMR (DMSO)δ: 10.94 (s, 1H), 8.94 (s, 1H), 8.48 (d, 1H, J=5.2 Hz), 8.00 (dd, 1H,J=2.5 Hz, J=12.8 Hz), 7.56 (bd, 1H, J=8.9 Hz), 7.52 (s, 1H), 7.48-7.35(m, 6H), 6.48 (d, 1H, J=4.9 Hz), 4.76 (s, 2H), 3.95 (s, 3H), 3.94 (s,3H), 1.44 (s, 9H).

Example 71

[5-[4-(6,7-Dimethoxyquinolin-4-yloxy)-3-fluorophenylcarbamoyl]-3-(4-fluorophenyl)-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl]-aceticacid. Example 70 was hydrolyzed using trifuoroacetic acid indichloromethane at room temperature for 18 to give Example 71 mp 225° C.dec.; LCMS m/z=605 (M+1); ¹H NMR (DMSO) δ: 13.42 (bs, 1H), 11.00 (s,1H), 8.95 (s, 1H), 8.72 (d, 1H, J=6.2 Hz), 8.07 (dd, 1H, J=2.5 Hz, J=13Hz), 7.69 (s, 1H), 7.62 (bd, 1H, J=8.6 Hz), 7.54 (t, 1H, J=9.1 Hz), 7.50(s, 1H), 7.44-7.34 (m, 4H), 6.84 (bs, 1H), 4.79 (s, 2H), 4.01 (s, 3H),4.00 (s, 3H).

Example 72

3-(4-Fluoro-phenyl)-1-oxazol-2-ylmethyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide. mp148-150° C.; LCMS m/z=628 (M+1); ¹H NMR (DMSO) δ: 10.85 (s, 1H), 9.05(s, 1H), 8.48 (d, 1H, J=5.2 Hz), 8.17 (s, 1H), 8.01 (dd, 1H, J=2.3 Hz,J=13 Hz), 7.56 (bd, 1H, J=8.5 Hz), 7.52 (s, 1H), 7.48-7.33 (m, 6H), 7.25(s, 1H), 6.48 (d, 1H, J=5.0 Hz), 5.41 (s, 2H), 3.95 (s, 3H), 3.94 (s,3H).

Example 73

3-(4-Fluoro-phenyl)-2,4-dioxo-1-(tetrahydro-furan-2-ylmethyl)-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide. mp127-130° C.; LCMS m/z=631 (M+1); ¹H NMR (DMSO) δ: 11.01 (s, 1H), 8.77(s, 1H), 8.48 (d, 1H, J=5.2 Hz), 8.01 (dd, 1H, J=2.3 Hz, J=13 Hz), 7.54(bd, 1H, J=9.5 Hz), 7.52 (s, 1H), 7.47-7.33 (m, 6H), 6.48 (d, 1H, J=5.3Hz), 4.17-4.09 (m, 2H), 3.99-3.93 (m, 1H), 3.95 (s, 3H), 3.94 (s, 3H),3.88-3.81 (m, 1H), 3.74-3.68 (m, 1H), 2.04-1.77 (m, 3H), 1.65-1.55 (m,1H).

Example 74

3-(4-Fluoro-phenyl)-2,4-dioxo-1-(tetrahydro-pyran-4-ylmethyl)-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide. mp185-187° C.; LCMS m/z=645 (M+1); ¹H NMR (DMSO) δ: 11.05 (s, 1H), 8.83(s, 1H), 8.48 (d, 1H, J=5.4 Hz), 8.01 (dd, 1H, J=2.4 Hz, J=13 Hz), 7.54(bd, 1H, J=8.6 Hz), 7.52 (s, 1H), 7.46-7.33 (m, 6H), 6.47 (bd, 1H, J=5.4Hz), 3.95 (s, 3H), 3.94 (s, 3H), 3.92-3.85 (m, 4H), 3.26 (bd, 2H, J=11.1Hz), 1.60 (bd, 2H, J=12.2 Hz), 1.32-1.23 (m, 3H).

Example 75

3-(4-Fluoro-phenyl)-1-(2-methyl-thiazol-4-ylmethyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide. mp196-198° C.; LCMS m/z=658 (M+1); ¹H NMR (DMSO) δ: 11.01 (s, 1H), 8.95(s, 1H), 8.48 (d, 1H, J=5.3 Hz), 8.01 (dd, 1H, J=2.3 Hz, J=12.5 Hz),7.55 (bd, 1H, J=9 Hz), 7.54 (s, 1H), 7.52 (s, 1H), 7.47-7.33 (m, 6H),6.48 (bd, 1H, J=5.9 Hz), 5.24 (s, 1H), 3.95 (s, 3H), 3.94 (s, 3H), 2.66(s, 3H).

Example 76

1-Cyclopentyl-3-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide. mp222-224° C.; LCMS m/z=615 (M+1); ¹H NMR (DMSO) δ: 11.03 (s, 1H), 8.63(s, 1H), 8.48 (d, 1H, J=5.4 Hz), 8.01 (dd, 1H, J=2.5 Hz, J=13 Hz), 7.54(bd, 1H, J=9 Hz), 7.52 (s, 1H), 7.46-7.33 (m, 6H), 6.48 (bd, 1H, J=5.4Hz), 4.90-4.81 (m, 1H), 3.95 (s, 3H), 3.94 (s, 3H), 2.12-2.04 (m, 2H),1.93-1.78 (m, 4H), 1.69-1.63 (m, 2H).

Example 77

1-Benzyl-3-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide. mp242-244° C.; LCMS m/z=637 (M+1); ¹H NMR (DMSO) δ: 11.01 (s, 1H), 8.97(s, 1H), 8.48 (d, 1H, J=5.8 Hz), 8.00 (dd, 1H, J=2.5 Hz, J=13 Hz), 7.54(bd, 1H, J=9 Hz), 7.52 (s, 1H), 7.47-7.33 (m, 11H), 6.47 (bd, 1H, J=5.4Hz), 5.22 (s, 2H), 3.95 (s, 3H), 3.94 (s, 3H).

Example 78

3-(4-Fluoro-phenyl)-1-[2-(2-fluoro-phenyl)-ethyl]-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide. mp178-180° C.; LCMS m/z=669 (M+1); ¹H NMR (DMSO) δ: 10.98 (s, 1H), 8.72(s, 1H), 8.48 (d, 1H, J=5.4 Hz), 7.98 (dd, 1H, J=2.4 Hz, J=13 Hz), 7.53(bd, 1H, J=9 Hz), 7.52 (s, 1H), 7.46-7.28 (m, 8H), 7.22-7.16 (m, 2H),6.47 (bd, 1H, J=5.3 Hz), 4.23 (t, 2H, J=7.4 Hz), 3.95 (s, 3H), 3.94 (s,3H), 3.07 (t, 2H, J=7.3 Hz).

Example 79

3-(4-Fluoro-phenyl)-1-[2-(4-fluoro-phenyl)-ethyl]-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide. mp203-205° C.; LCMS m/z=669 (M+1); ¹H NMR (DMSO): 11.00 (s, 1H), 8.79 (s,1H), 8.48 (d, 1H, J=5.4 Hz), 7.99 (dd, 1H, J=2.4 Hz, J=13 Hz), 7.53 (bd,1H, J=9 Hz), 7.52 (s, 1H), 7.47-7.33 (m, 8H), 7.20-7.14 (m, 2H), 6.47(bd, 1H, J=5.3 Hz), 4.18 (t, 2H, J=7.4 Hz), 3.95 (s, 3H), 3.94 (s, 3H),3.01 (t, 2H, J=7.3 Hz).

Example 80

1-(2-Cyclohexyl-ethyl)-3-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide. mp186-190° C.; LCMS m/z=657 (M+1); ¹H NMR (DMSO) δ: 11.04 (s, 1H), 8.86(s, 1H), 8.48 (d, 1H, J=5.2 Hz), 8.01 (dd, 1H, J=2.3 Hz, J=13 Hz), 7.54(bd, 1H, J=9.5 Hz), 7.52 (s, 1H), 7.46-7.27 (m, 6H), 6.48 (d, 1H, J=5.3Hz), 4.00 (t, 2H, J=7.2 Hz), 3.95 (s, 3H), 3.94 (s, 3H), 1.75-1.57 (m,8H), 1.23-1.15 (m, 3H), 0.99-0.90 (m, 2H).

Example 81

3-(4-Fluoro-phenyl)-2,4-dioxo-1-(3-phenyl-propyl)-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide. mp128-131° C.; LCMS m/z=665 (M+1); ¹H NMR (DMSO) δ: 11.02 (s, 1H), 8.84(s, 1H), 8.48 (d, 1H, J=5.4 Hz), 8.01 (dd, 1H, J=2.5 Hz, J=10 Hz), 7.54(bd, 1H, J=11 Hz), 7.52 (s, 1H), 7.46-7.16 (m, 11H), 6.48 (d, 1H, J=4.9Hz), 4.03 (t, 2H, J=7.2 Hz), 3.95 (s, 3H), 3.94 (s, 3H), 2.68 (dd, 2H,J=7.2 Hz, J=16 Hz), 2.03 (t, 2H, J=7.2 Hz).

Example 82

3-(4-Fluoro-phenyl)-2,4-dioxo-1-(2-oxo-2-pyrrolidin-1-yl-ethyl)-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide. mp189-192° C.; LCMS m/z=658 (M+1); ¹H NMR (DMSO) δ: 10.97 (s, 1H), 8.80(s, 1H), 8.48 (d, 1H, J=5.3 Hz), 8.00 (dd, 1H, J=2.4 Hz, J=12 Hz), 7.56(bd, 1H, J=8.5 Hz), 7.53 (s, 1H), 7.47-7.35 (m, 6H), 6.48 (d, 1H, J=5.2Hz), 4.88 (s, 2H), 3.95 (s, 3H), 3.94 (s, 3H), 3.48 (t, 2H, J=6.6 Hz),3.35 (t, 2H, J=6.9 Hz), 1.93 (p, 2H, J=6.7 Hz), 1.80 (p, 2H, J=6.9 Hz).

Example 83

1-Dimethylcarbamoylmethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluorophenyl]-amide. mp163-166° C.; LCMS m/z=632 (M+1); ¹H NMR (DMSO) δ: 10.96 (s, 1H), 8.79(s, 1H), 8.48 (d, 1H, J=5.0 Hz), 8.00 (dd, 1H, J=2.5 Hz, J=13 Hz), 7.56(bd, 1H, J=9.4 Hz), 7.53 (s, 1H), 7.47-7.35 (m, 6H), 6.48 (d, 1H, J=5.4Hz), 4.97 (s, 2H), 3.95 (s, 3H), 3.94 (s, 3H), 3.03 (s, 3H), 2.89 (s,3H).

Example 84

1-(1-Dimethylcarbamoyl-2-oxo-propyl)-3-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide. mp137-140° C.; LCMS m/z=674 (M+1); ¹H NMR (DMSO) δ: 10.93 (s, 1H), 8.56(s, 1H), 8.48 (d, 1H, J=5.3 Hz), 8.00 (dd, 1H, J=2.3 Hz, J=13 Hz), 7.55(bd, 1H, J=9 Hz), 7.52 (s, 1H), 7.47-7.33 (m, 6H), 6.72 (s, 1H), 6.48(d, 1H, J=5.7 Hz), 3.95 (s, 3H), 3.94 (s, 3H), 3.17 (s, 3H), 2.97 (s,3H), 2.31 (s, 3H).

Example 85

Step a. 4-(6,7-Dimethoxyquinolin-4-yloxy)-2-fluoro-phenylamine. Amixture of 3-fluoro-4-nitrophenol (0.644 g, 4.10 mmol) and 60% sodiumhydride (0.215 g, 5.60 mmol) in dimethylformamide (20 mL) was stirred 15min. 4-Bromo-6,7-dimethoxyquinoline (1.0 g, 3.73 mmol) was added and themixture stirred at 110° C. for 18 h. After partitioning between waterand ethyl acetate, the organics were washed with water and brine. Thesolvent was removed under vacuum, and the residue was purified by columnchromatography (0-5% methanol in dichloromethane).

Step b. The nitro intermediate (0.52 g, 1.51 mmol) from step a inethanol (20 mL) was hydrogenated on a Parr apparatus at 50 psi with 10%palladium on carbon (0.05 g) for 4 h. The solution was filtered and theproduct purified by column chromatography (0-5% MeOH in dichloromethane)to give 4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenylamine in 36%yield. ¹H NMR (DMSO) δ: 8.80 (d, 1H, J=6.5 Hz), 7.72 (s, 1H), 7.70 (s,1H), 7.26 (dd, 1H, J=2.6 Hz, J=12 Hz), 7.03-6.96 (m, 2H), 6.90 (d, 1H,J=6.5 Hz), 4.69 (bs, 2H), 4.04 (s, 3H), 4.03 (s, 3H).

The following examples were synthesized using4-(6,7-dimethoxy-quinolin-4-yloxy)-2-fluorophenylamine and the methodfor Example 1.

3-(4-Fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-2-fluoro-phenyl]-amide. mp238-243° C.; LCMS m/z=547 (M+1); ¹H NMR (DMSO) δ: 12.44 (bs, 1H), 11.16(bs, 1H), 8.52-8.46 (m, 3H), 7.47 (s, 1H), 7.44-7.33 (m, 5H) 7.40 (s,1H), 7.14 (d, 1H, J=9.0 Hz), 6.59 (d, 1H, J=5.0 Hz), 3.95 (s, 3H), 3.92(s, 3H).

Example 86

3-(4-Fluoro-phenyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-2-fluoro-phenyl]-amide. mp208-210° C.; LCMS m/z=561 (M+1); ¹H NMR (DMSO) δ: 11.17 (bs, 1H), 8.90(s, 1H), 8.51-8.46 (m, 2H), 7.47 (s, 1H), 7.43-7.34 (m, 6H) 7.40 (s,1H), 7.16 (d, 1H, J=9.0 Hz), 6.59 (d, 1H, J=5.0 Hz), 3.95 (s, 3H), 3.92(s, 3H), 3.54 (s, 3H).

Example 87

1-Ethyl-3-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-2-fluoro-phenyl]-amide. mp142-144° C.; LCMS m/z=575 (M+1); ¹H NMR (DMSO) δ: 11.18 (bs, 1H), 8.91(s, 1H), 8.50 (d, 1H, J=5.2 Hz), 8.48 (t, 1H, J=9.8 Hz), 7.47 (s, 1H),7.45-7.33 (m, 6H), 7.16 (bd, 1H, J=8.3 Hz), 6.59 (d, 1H, J=5.2 Hz), 4.02(q, 2H, J=7.0 Hz), 3.95 (s, 3H), 3.92 (s, 3H), 1.30 (t, 3H, J=7.0 Hz).

Example 88

1-Allyl-3-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-2-fluoro-phenyl]-amide. mp134-136° C.; LCMS m/z=587 (M+1); ¹H NMR (DMSO) δ: 11.16 (s, 1H), 8.82(s, 1H), 8.50 (d, 1H, J=5.5 Hz), 8.47 (t, 1H, J=8.0 Hz), 7.47 (s, 1H),7.46-7.34 (m, 6H), 7.16 (bd, 1H, J=8.6 Hz), 6.59 (d, 1H, J=5.4 Hz),6.03-5.93 (m, 1H), 5.38 (d, 1H, J=17 Hz), 5.29 (d, 1H, J=10.6 Hz), 4.63(d, 2H, J=5.7 Hz), 3.95 (s, 3H), 3.92 (s, 3H).

Example 89

3-(4-Fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3,5-difluoro-phenyl]-amide.Example 89 was synthesized using the4-(6,7-dimethoxyquinolin-4-yloxy)-3,5-difluorophenylamine (synthesizedusing the method for example 85 starting with2,6-difluoro-4-nitrophenol; LCMS m/z=333 M+1); LCMS m/z=565 (M+1); ¹HNMR (CDCl₃) δ: 8.50 (bd, 1H), 8.47 (s, 1H), 7.60 (d, 1H, J=4.0 Hz), 7.46(bd, 2H, J=15 Hz), 7.24-7.12 (m, 6H), 6.36 (d, 1H, J=8.9 Hz), 5.88 (d,1H, J=8.1 Hz), 4.07 (s, 3H), 4.05 (s, 3H).

Example 90

1-Ethyl-3-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3,5-difluoro-phenyl]-amide. mp166-170° C.; LCMS m/z=593 (M+1); ¹H NMR (DMSO) δ: 11.13 (s, 1H), 8.91(s, 1H), 8.50 (d, 1H, J=6.8 Hz), 7.83 (d, 2H, J=9.8 Hz), 7.54 (s, 1H),7.45-7.32 (m, 5H), 6.59 (d, 1H, J=6.5 Hz), 4.02 (q, 2H, J=6.5 Hz), 3.96(s, 6H), 2.69 (t, 3H, J=6.5 Hz).

Example 91

3-Ethyl-1-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide. To asolution of 4-fluoroaniline (1.0 g, 9.01 mmol) in THF (20 mL) at 0° C.,was slowly added ethyl isocyanate (0.70 g, 10.0 mmol). After stirring 30min. at 0° C., the solution was warmed to rt and the solvent was removedunder vacuum. To the residue was added ethanol (30 mL), diethylethoxymethylenemalonate (1.95 g, 9.01 mmol) and 21% NaOEt in ethanol(2.92 mL, 9.01 mmol)) and the reaction stirred 48 h at rt. The solventwas removed under vacuum and cold conc. HCl was added to pH 6. Theaqueous layer was removed under vacuum and the solids were crystallizedfrom ethyl acetate and hexanes.3-Ethyl-1-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid ethyl ester isomer was isolated in 25% yield. ¹H NMR (CDCl₃) δ:8.32 (s, 1H), 7.20-7.14 (m, 4H), 4.35 (q, 2H, J=7.1 Hz), 3.95 (q, 2H,J=7.2 Hz), 1.42 (t, 3H, J=7.2 Hz), 1.36 (t, 3H, J=7.2 Hz).3-Ethyl-1-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid ethyl ester was hydrolyzed with 1N LiOH in MeOH and THF at 65° C.The acid was coupled with4-(6,7-Dimethoxyquinolin-4-yloxy)-3-fluorophenylamine using the methodfor example 1 to give3-ethyl-1-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide mp140-142° C.; LCMS m/z=575 (M+1); ¹H NMR (DMSO) δ: 11.18 (s, 1H), 8.49(d, 1H, J=2.5 Hz), 8.46 (s, 1H), 8.03 (dd, 1H, J=3 Hz, J=13 Hz),7.65-7.39 (m, 6H), 7.55 (s, 1H), 7.41 (s, 1H), 6.49 (d, 1H, J=5.0 Hz),4.00 (q, 2H, J=7.4 Hz), 3.95 (s, 6H), 1.23 (t, 3H, J=7.3 Hz).

Example 92

1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid[4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluorophenyl]-amide

Step a. A mixture of 2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid ethyl ester (0.100 g, 0.543 mmol), iodomethane (0.130 mL, 1.63mmol), and potassium carbonate (0.225 g, 1.63 mmol) was slurred inN,N-dimethylformamide (5 mL, 60 mmol) at 80° C. 18 h. The mixture waspoured into water and extracted with ethyl acetate. The residue washydrolyzed with 1 equivalent of 1N LiOH in THF/MeOH (1:1; 6 mL) at 60°C. 4 h. The organics were removed under vacuum, and the aqueous waswashed with ethyl acetate. The aqueous was then cooled and acidifiedwith conc. HCl. The1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acidwas filtered off in 60% yield. ¹H NMR (DMSO) δ: 12.78 (bs, 1H), 8.72 (s,1H), 3.45 (s, 3H), 3.22 (s, 3H).

This intermediate acid was coupled with4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenylamine as described inexample 1. mp 258-260° C.; LCMS m/z=481 (M+1); ¹H NMR (DMSO) δ: 11.22(s, 1H), 8.76 (s, 1H), 8.49 (d, 1H, J=5.3 Hz), 8.02 (dd, 1H, J=2.5 Hz,J=13 Hz), 7.54 (d, 1H, J=8 Hz), 7.54 (s, 1H), 7.47 (t, 1H, J=9.0 Hz),7.41 (s, 1H), 6.49 (d, 1H, J=9.0 Hz), 3.95 (s, 6H), 3.51 (s, 3H), 3.29(s, 3H).

Examples 92-98 intermediate acids were synthesized as in Scheme 2 anddescribed in Example 92 and coupled using methods described for Example1.

Example 93

1,3-Diethyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid[4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide. mp 178-180°C.; LCMS m/z=509 (M+1); ¹H NMR (DMSO) δ: 11.22 (s, 1H), 8.76 (s, 1H),8.49 (d, 1H, J=5.5 Hz), 8.02 (dd, 1H, J=2.5 Hz, J=13 Hz), 7.55 (d, 1H,J=8 Hz), 7.54 (s, 1H), 7.46 (t, 1H, J=9.0 Hz), 7.41 (s, 1H), 6.49 (d,1H, J=9.0 Hz), 4.02-3.96 (m, 4H), 3.95 (s, 6H), 1.27 (t, 3H, J=7.4 Hz),1.18 (t, 3H, J=7.5 Hz).

Example 94

1,3-Diisopropyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide. mp113-116° C.; LCMS m/z=537 (M+1); ¹H NMR (DMSO) δ: 11.22 (s, 1H), 8.54(s, 1H), 8.49 (d, 1H, J=5.0 Hz), 8.02 (dd, 1H, J=2.5 Hz, J=13 Hz), 7.54(bd, 1H, J=9 Hz), 7.53 (s, 1H), 7.46 (t, 1H, J=8.1 Hz), 7.42 (s, 1H),6.49 (d, 1H, J=5.6 Hz), 5.18 (h, 1H, J=6.7 Hz), 4.78 (h, 1H, J=6.8 Hz),3.95 (s, 6H), 1.45 (d, 6H, J=6.7 Hz), 1.38 (d, 6H, J=6.4 Hz).

Example 95

1,3-Bis-cyclopropylmethyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide. mp63-65° C.; LCMS m/z=561 (M+1); ¹H NMR (DMSO) δ: 11.192 (s, 1H), 8.83 (s,1H), 8.49 (d, 1H, J=5.3 Hz), 8.03 (dd, 1H, J=2.3 Hz, J=13.5 Hz), 7.55(bd, 1H, J=9 Hz), 7.54 (s, 1H), 7.46 (t, 1H, J=8.9 Hz), 7.41 (s, 1H),6.49 (d, 1H, J=5.1 Hz), 3.95 (s, 6H), 3.84 (t, 4H, J=7.1 Hz), 1.16-1.08(m, 2H), 0.56-0.38 (m, 8H).

Example 96

1,3-Diallyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid[4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide. mp 172-174°C.; LCMS m/z=529 (M+1); ¹H NMR (DMSO) δ: 11.10 (s, 1H), 8.72 (s, 1H),8.49 (d, 1H, J=5.2 Hz), 8.02 (dd, 1H, J=2.5 Hz, J=13 Hz), 7.56 (bd, 1H,J=8.9 Hz), 7.53 (s, 1H), 7.46 (t, 1H, J=8.8 Hz), 6.49 (d, 1H, J=5.2 Hz),6.03-5.03 (m, 2H), 5.31-5.27 (m, 1H), 5.27-5.25 (m, 1H), 5.20-5.17 (m,1H), 5.16-5.14 (m, 1H), 4.60 (d, 2H, J=5.5 Hz), 4.53 (d, 2H, J=5.5 Hz),3.95 (s, 3H), 3.94 (s, 3H).

Example 97

1,3-Bis-(3-methyl-but-2-enyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide. mp184-186° C.; LCMS m/z=589 (M+1); ¹H NMR (DMSO) δ: 11.15 (s, 1H), 8.65(s, 1H), 8.49 (d, 1H, J=5.7 Hz), 8.02 (dd, 1H, J=2. Hz, J=13 Hz), 7.54(bd, 1H, J=9 Hz), 7.52 (s, 1H), 7.46 (t, 1H, J=9.5 Hz), 7.71 (s, 1H),6.49 (bd, 1H, J=5 Hz), 5.30 (m, 1H), 5.19 (m, 1H), 4.53 (dd, 4H, J=6.7Hz, J=15.3 Hz), 3.95 (s, 6H), 1.78 (bs, 3H), 1.77 (bs, 3H), 1.74 (bs,3H), 1.69 (bs, 3H).

Example 98

2,4-Dioxo-1,3-di-prop-2-ynyl-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide. mp133-138° C.; LCMS m/z=529 (M+1); ¹H NMR (DMSO) δ: 10.94 (s, 1H), 8.88(s, 1H), 8.49 (d, 1H, J=6.5 Hz), 8.03 (dd, 1H, J=2.5 Hz, J=13 Hz), 7.59(bd, 1H, J=8.5 Hz), 7.54 (s, 1H), 7.48 (t, 6H, J=9.1 Hz), 6.50 (d, 1H,J=5.3 Hz), 4.84 (d, 2H, J=2.4 Hz), 4.42 (d, 2H, J=2.2 Hz), 3.96 (s, 6H),3.61 (t, 1H, J=2.5 Hz), 3.25 (t, 1H, J=2.5 Hz).

Example 99

2,4-Dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid[4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide. A solutionof 2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid (0.156 g,1.00 mmol) in thionyl chloride (2 mL, 30 mmol) was stirred at 100° C. 3h. After the solvent was removed under vacuum,[4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenylamine (0.314 g, 1.00mmol) and pyridine (2 mL, 20 mmol) were added and stirred at roomtemperature 18 hr. The solvent was removed under vacuum and the residuewas purified on HPLC. 0.15 g of the trifluoracetic acid salt wasisolated in 27% yield. mp 251-255° C.; LCMS m/z=453 (M+1); ¹H NMR (DMSO)δ: 11.99 (bs, 1H), 11.93 (s, 1H), 11.18 (s, 1H), 8.74 (d, 1H, J=4.5 Hz),8.31 (d, 1H, J=7.5 Hz), 8.06 (d, 1H, J=12 Hz), 7.70 (s, 1H), 7.55 (m,2H), 7.51 (s, 1H), 6.85 (m, 1H), 4.02 (s, 3H), 4.01 (s, 3H).

Example 100

1-Ethyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide. To asolution of 2-aminomethylene-malonic acid diethyl ester (0.75 g, 4.0mmol) and phenyl isocyanate (0.57 g, 4.4 mmol) in 1,2-dichloroethane (20mL) was added N,N-diisopropylethylamine (0.77 mL, 4.4 mmol) and heatedat 100° C. 6 h. The mixture was cooled and filtered. The solids werepurified by column chromatography with 0-5% MeOH in methylene chloride.This intermediate urea was suspended in ethanol (10 mL) and 21% NaOEt inethanol (1.29 mL, 4.0 mmol) was added. After 18 h the solvent wasremoved under vacuum and the residue was slurred in ethyl acetate. Theorganics were washed with 1M citric acid solution, water and brine. Thesolvent was removed under vacuum and the residue was purified bychromatography with 0-5% MeOH in dichloromethane to give 0.50 g (40%).The ester was alkylated and hydrolyzed using methods for example 92 togive1-ethyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid. ¹H NMR (DMSO) δ: 12.65 (bs, 1H), 8.82 (s, 1H), 7.54-7.43 (m, 3H),7.32-7.29 (m, 2H), 4.02 (q, 2H, J=7.1 Hz), 1.26 (t, 3H, J=7.1 Hz).

This intermediate acid was coupled to4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenylamine as described inexample 1 to give Example 100. mp 282-285° C.; LCMS m/z=557 (M+1); ¹HNMR (DMSO) δ: 11.01 (s, 1H), 8.89 (s, 1H), 8.48 (d, 1H, J=4.6 Hz), 8.00(dd, 1H, J=2.3 Hz, J=13 Hz), 7.56-7.34 (m, 9H), 6.47 (d, 1H, J=4.6 Hz),4.02 (q, 2H, J=6.9 Hz), 3.95 (s, 3H), 3.94 (s, 3H), 1.3 (t, 3H, J=7.4Hz).

Example 101

1-Isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide. mp235-237° C.; LCMS m/z=571 (M+1); ¹H NMR (DMSO) δ: 11.07 (s, 1H), 8.69(s, 1H), 8.48 (d, 1H, J=4.6 Hz), 8.01 (dd, 1H, J=2.3 Hz, J=13 Hz),7.55-7.35 (m, 9H), 6.48 (d, 1H, J=4.6 Hz), 4.79 (h, 1H, J=6.9 Hz), 3.95(s, 3H), 3.94 (s, 3H), 1.43 (d, 6H, J=6.8 Hz).

Example 102

3-(4-Fluoro-phenyl)-2,4-dioxo-1-propyl-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid [4-(6,7-dimethoxy-quinoline-4-carbonyl)-3-fluoro-phenyl]-amide

Step a. A solution of 4-bromo-6,7-dimethoxyquinoline (1.0 g, 3.73 mmol)in dry THF (20 mL) was cooled to −78° C. A solution of 2.5Mn-butyllithium in hexanes (1.50 mL, 3.73 mmol) was added and stirred 15min. A solution of 4-bromo-2-fluoro-benzaldehyde (0.757 g, 3.73 mmol) inTHF (10 mL) was added dropwise over 5 min. After stirring 30 min. at−78° C., saturated ammonium chloride solution (1 mL) was added. Thesolvent was removed under reduced pressure. The residue was dissolved inethyl acetate and washed with water. After the solvent was removed undervacuum, the residue was purified by chromatography with 0-5% MeOH indichloromethane to give(4-bromo-2-fluoro-phenyl)-(6,7-dimethoxy-quinolin-4-yl)-methanol in 52%yield. ¹H NMR (CDCl₃) δ: 8.63 (d, 1H, J=4.1 Hz), 7.57 (d, 1H, J=4.7 Hz),7.34 (s, 1H), 7.25-7.17 (m, 2H), 7.08 (s, 1H), 6.67 (s, 1H), 4.02-3.96(m, 1H), 3.94 (s, 3H), 3.88 (s, 3H).

Step b. The intermediate from step a (0.196 g, 0.50 mmol) was dissolvedin THF (5 mL) and 1M lithium hexamethyldisilazane in THF (0.55 mL, 0.55mmol), bis(dibenzylideneacetone)palladium (0.014 g, 5 mol %) andtri-tert-butylphosphine (0.061 mL, 5 mol %) were added. The sealed tubewas heated at 65° C. 18 hr. After cooling, concentrated HCl was added topH 1 and stirred 1 hr. The solvent was removed under vacuum, ethylacetate and saturated sodium bicarbonate solution was added untilslightly basic. The organics were separated, the solvent removed undervacuum and the residue purified by chromatography with 0-5% MeOH indichloromethane to give(4-amino-2-fluoro-phenyl)-(6,7-dimethoxy-quinolin-4-yl)methanone in 60%yield. ¹H NMR (CDCl₃) δ: 8.78 (d, 1H, J=4.7 Hz), 7.69 (d, 1H, J=4.7 Hz),7.42 (s, 1H), 7.10 (s, 1H), 6.90 (t, 1H, J=8.3 Hz), 6.65 (s, 1H), 6.41(dd, 1H, J=2.2 Hz, J=12.1 Hz), 6.33 (dd, 1H, J=2.2 Hz, J=8.4 Hz), 4.00(s, 3H), 3.90 (s, 3H), 3.80 (bs, 2H), 2.33 (bs, 1H).

Steps c and d.3-(4-Fluoro-phenyl)-2,4-dioxo-1-propyl-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid [4-(6,7-dimethoxy-quinoline-4-carbonyl)-3-fluoro-phenyl]-amide. Theintermediate from step b was coupled with3-(4-fluorophenyl)-2,4-dioxo-1-propyl-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid using the methods for Example 1. The alcohol (0.075 g, 0.12 mmol)product was dissolved in dichloromethane (5 mL) and cooled to 0° C.Dess-Martin periodinane (0.076 g, 0.18 mmol) was added slowly and thesolution warmed to room temperature for 4 h. The organics were washedwith saturated sodium bicarbonate and the solvent removed under vacuum.The residue was purified by column chromatography with 5% MeOH indichloromethane to give 0.063 g (84%) mp 125-127° C.; LCMS m/z=601(M+1); ¹H NMR (DMSO) δ: 11.30 (s, 1H), 8.88 (s, 1H), 8.79 (d, 1H, J=4.0Hz), 7.87 (dd, 1H, J=1.9 Hz, J=13 Hz), 7.72 (t, 1H, J=8.5 Hz), 7.56 (dd,1H, J=1.8 Hz, J=8.7 Hz), 7.49 (s, 1H), 7.45-7.32 (m, 5H), 7.29 (s, 1H),3.96 (s, 3H), 3.94 (t, 2H, J=7.4 Hz), 3.77 (s, 3H), 1.71 (q, 2H, J=7.8Hz), 0.92 (t, 3H, J=8.3 Hz).

Synthesis of 3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylicacid Method A

Step a.4-(4-fluorophenyl)-5-oxo-3-thioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylicacid ethyl ester. A mixture of 2-oxo-malonic acid diethyl ester (2.5 mL,16 mmol) and 4-fluorophenyl thiosemicarbazide (3.0 g, 16 mmol) inethanol (60 mL, 1000 mmol) was heated at reflux for 3 days. The mixturewas cooled to rt and the separated solid was filtered, washed with coldethanol and dried to give 3.44 g (71%). LCMS m/z=296 (M+1); ¹H NMR(DMSO) δ: 7.35 (m, 4H), 4.30 (q, 2H, J=7.1 Hz), 1.27 (t, 3H, J=7.1 Hz).

Step b.4-(4-Fluorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylicacid ethyl ester. To a solution of4-(4-fluorophenyl)-5-oxo-3-thioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylicacid ethyl ester (11 g, 37 mmol) in N,N-dimethylformamide (100 mL) andacetic acid (40 mL, 700 mmol) was added 50% aq. hydrogen peroxide (11mL, 190 mmol). The mixture was stirred at rt 2 days, the solvent wasremoved and the product was taken up in ethylacetate and washedsuccessively with water and brine. After drying, the solvent wasevaporated. The solid obtained was triturated with ether, filtered andwashed with cold ether to yield 9.85 g (95%). LCMS m/z=280 (M+1); ¹H NMR(DMSO) δ: 13.1 (s, 1H), 7.42-7.28 (2m, 4H), 4.29 (q, 2H, J=7.1 Hz), 1.27(t, 3H, J=7.1 Hz).

Step c.4-(4-Fluorophenyl)-2-isopropyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylicacid ethyl ester.4-(4-Fluorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylicacid ethyl ester (1000 mg, 4 mmol), isopropyl iodide (0.72 mL, 7.16mmol) and potassium carbonate (544 mg, 3.94 mmol) inN,N-dimethylformamide (20 mL) was heated at 65° C. for 60 min. Thereaction mixture was cooled to rt and was concentrated, diluted withEtOAc and was filtered through a pad of celite. The filtrate wasconcentrated and the product purified by flash chromatography(hexane:EtOAc 3:1) to give a white solid (1.1 g, 96%). LCMS m/z=322(M+1); ¹H NMR (DMSO) δ: 7.41-7.31 (m, 4H), 4.86 (m, 1H), 4.31 (q, 2H,J=7.0 Hz), 1.31-1.26 (overlapping t and d, 9H).

Step d.4-(4-Fluorophenyl)-2-isopropyl-3,5-dioxo-2,3,4,5-tetrahydro[1,2,4]triazine-6-carboxylicacid. Sulfuric acid (10 mL, 200 mmol) was carefully added to a mixtureof4-(4-fluorophenyl)-2-isopropyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylicacid ethyl ester (1100 mg, 3.4 mmol) and water (2 mL). The mixturebecame homogenous after a few minutes. The reaction mixture was stirredat 40° C. overnight, was cooled to rt and was carefully added to ice.The mixture was saturated with solid NaCl and was extracted repeatedlyfrom EtOAc (3×). The combined EtOAc layer was washed with brine, driedover magnesium sulfate, and concentrated to give the product as foam(100%). LCMS m/z=294 (M+1); ¹H NMR (Methanol d4) a: 7.35-7.31 (2m, 4H),4.95 (m, 1H), 4.31 (q, 2H, J=7.0 Hz), 1.41 (d, 6H, J=6.6 Hz).

The following 3,5-dioxo-2,3,4,5-tetrahydro[1,2,4]triazine-6-carboxylicacids were synthesized using the previous procedure.

2-Ethyl-4-(4-fluorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylicacid. LCMS m/z=280 (M+1); 1H NMR (Methanol-d4) a: 7.34-7.18 (m, 4H),4.10 (q, 2H, J=7.2 Hz), 1.38 (t, 3H, J=7.2 Hz).

4-(4-Fluorophenyl)-2-(2-hydroxyethyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylicacid. Synthesized from2-[2-(t-butyldimethylsilanyloxy)ethyl]-4-(4-fluorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylicacid. LCMS m/z=296 (M+1); ¹H NMR (DMSO) δ: 7.41-7.36 (m, 4H), 4.09-4.01(2m, 3H), 3.72 (m, 2H).Tert-4-(4-Fluorophenyl)-3,5-dioxo-2-(2-oxo-propyl)-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylicacid. (from the ester precursor,4-(4-fluorophenyl)-3,5-dioxo-2-prop-2-ynyl-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylicacid ethyl ester). LCMS m/z=308 (M+1); ¹H NMR (DMSO) δ: 7.46-7.32 (m,4H), 4.95 (s, 2H2.21 (s, 3H).

2-Cyclopropylmethyl-4-(4-fluoro-phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylicacid. LCMS m/z=306 (M+1.

4-(4-Fluorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylicacid.4-(4-Fluoro-phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylicacid ethyl ester (300 mg, 1 mmol) in THF (3 mL) and MeOH (7 mL) wasadded 5M NaOH (2 mL, 2 mmol). The mixture was stirred at rt for 1 h andwas concentrated. Water was added and the mixture was extracted withether. The aq. layer was made acidic with HCl at 0° C. and was extractedwith EtOAc and concentrated. LCMS m/z=274 (M+Na); ¹H NMR (DMSO) δ: 13.03(s, 1H), 7.35-7.30 (m, 4H).

Method B

Step a.4-(4-Fluoro-phenyl)-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylicacid. To a mixture of2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylic acidethyl ester (220 mg, 1.1 mmol) (Yuen, K. J Org. Chem. 1962, 27, 976),4-Fluorophenyl boronic acid (230 mg, 1.6 mmol) and triethylamine (0.46mL, 3.3 mmol) in methylene chloride (5 mL, 80 mmol) was added copperacetate (150 mg, 1.2 mmol). The mixture was stirred under argon at rt 18h. The solvent was removed and the product was purified by flashchromatography (hexane:EtOAc 60:40) to yield 34 mg (10%). LCMS=294(M+1).

Step b.4-(4-Fluorophenyl)-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylicacid.4-(4-fluorophenyl)-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylicacid ethyl ester (30 mg, 0.1 mmol) was dissolved in THF-MeOH (1:1, 2 mL)and 1M of lithium hydroxide (0.102 mL, 0.102 mmol) was added. Afterstirring at rt overnight, the solution was concentrated, dissolved in 1NNa₂CO₃ and washed with EtOAc. The aqueous layer was filtered and madeacidic with 5N HCl and extracted with EtOAc. The combined organics werewashed with water and brine, dried (MgSO4) and evaporated to give awhite solid (30 mg, 100%). LCMS m/z=266 (M+1); ¹H NMR (Methanol d4):7.55-7.52 (m, 2H), 7.07-7.03 (m, 2H), 3.52 (s, 3H).

Example 103

4-(4-Fluoro-phenyl)-2-isopropyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide. Amixture of4-(4-fluorophenyl)-2-isopropyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylicacid (500 mg, 2 mmol),4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenylamine (535 mg, 1.70mmol), N,N,N′,N-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (639 mg, 1.68 mmol) and N,N-diisopropylethylamine(279 uL, 1.60 mmol) in N,N-dimethylformamide (8 mL) was stirred at rtfor 3 h. The solvent was removed and the residue dissolved in EtOAc andwashed with saturated NaHCO₃ solution water and brine. After drying overmagnesium sulfate, solvent was evaporated and the product was purifiedby ISCO silica gel chromatography (hexane:EtOAc 1:4) to give 835 mg(83%), which triturated with ether and dried. mp=225-226° C.; LCMSm/z=590 (M+1); ¹H NMR DMSO) δ: 10.87 (s, 1H), 8.49 (d, 1H, J=5.2 Hz),7.97 (dd, 1H, J=12.6, 2.2 Hz), 7.59-7.36 (m, 8H), 6.50 (d, 1H, J=4.9Hz), 4.90 (m, 1H), 3.95 (s, 6H), 3.32 (s, 3H), 1.38 (d, 6H, J=6.6 Hz).

The following examples were synthesized using the procedure for Example103.

Example 104

4-(4-Fluorophenyl)-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide TFAsalt. The product was purified by reverse phase HPLC (Gilson) and thefractions showing product were concentrated as the TFA salt to give anoff-white solid. LCMS m/z=562 (M+1); ¹H NMR (DMSO) δ: 10.98 (s, 1H),8.74 (d, 1H, J=6.1 Hz), 8.02 (dd, 1H, J=12.7, 2.3 Hz), 7.70 (s, 1H),7.67-7.56 (2m, 2H), 7.52 (s, 1H), 7.43-7.37 (m, 4H), 6.88 (d, 1H, J=5.5Hz), 4.02 (s, 3H), 4.01 (s, 3H), 3.69 (s, 3H).

Example 105

2-Ethyl-4-(4-fluoro-phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide TFAsalt. off-white solid, LCMS m/z=576 (M+1); 1H NMR (DMSO) δ: 10.99 (s,1H), 8.78 (d, 1H, J=6.2 Hz), 8.03 (dd, 1H, J=12.7, 2.3 Hz), 7.72 (s,1H), 7.67-7.58 (m, 2H), 7.54 (s, 1H), 7.45-7.32 (2 m, 4H), 6.93 (d, 1H,J=6.1 Hz), 4.08 (q, 2H, J=7.1 Hz), 4.03 (s, 3H), 4.02 (s, 3H), 1.35 (t,3H, J=7.1 Hz).

Example 106

4-(4-Fluorophenyl)-2-isopropyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylicacid[4-(2,3-dihydro-[1,4]dioxino[2,3-g]quinolin-9-yloxy)-3-fluorophenyl]-amideTFA salt. This compound was synthesized from4-(2,3-dihydro[1,4]dioxino[2,3-g]quinolin-9-yloxy)-3-fluorophenylamine;hydrochloride (synthesized using the procedure for example 111 step a;LCMS m/z=313 (M+1); ¹H NMR (DMSO) δ: 8.85 (d, 1H, J=6.5 Hz), 7.87 (s,1H), 7.76 (s, 1H), 7.26 (t, 1H, J=8.9 Hz), 6.88 (dd, 1H, J=6.6, 0.8 Hz),6.78 (dd, 1H, J=8.6, 1.9 Hz), 6.67 (br d, 1H, J=8.6 Hz), 4.52 (m, 4H))and4-(4-fluorophenyl)-2-isopropyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylicacid using the procedure for example 103 to give an off-white solid,LCMS m/z=588 (M+1); ¹H NMR (DMSO) δ: 10.94 (s, 1H), 8.74 (d, 1H, J=6.0Hz), 8.02 (dd, 1H, J=12.6, 2.3 Hz), 7.80 (s, 1H), 7.63-7.53 (2m & s,3H), 7.54 (s, 1H), 7.45-7.36 (m, 4H), 6.81 (d, 1H, J=5.9 Hz), 4.90 (q,1H, J=6.6 Hz), 4.48 (m, 4H), 1.38 (d, 6H, J=6.6 Hz).

Example 107

4-(4-Fluoro-phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide TFAsalt. Off-white solid, LCMS m/z=548 (M+1); 1H NMR DMSO) δ: 13.30 (s,1H), 10.97 (s, 1H), 8.71 (d, 1H, J=6.0 Hz), 8.02 (dd, 1H, J=12.7, 2.3Hz), 7.68 (s, 1H), 7.65 (m, 1H), 7.65 (m, 1H), 7.56 (m, 1H), 7.5 (s,1H), 7.46-7.31 (2 m, 4H), 6.83 (d, 1H, J=6.3 Hz), 4.01 (s, 6H).

Example 108

4-(4-Fluorophenyl)-2-(2-hydroxyethyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylicacid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide. TFA saltOff-white solid; LCMS m/z=592 (M+1); ¹H NMR DMSO) δ: 10.96 (s, 1H), 8.75(d, 1H, J=6.2 Hz), 8.02 (dd 1H, J=12.6, 2.4 Hz), 7.70 (s, 1H), 7.66-7.57(m, 2H), 7.51 (s, 1H), 7.41-7.39 (m and s, 4H), 6.89 (d, 1H, J=5.4 Hz),4.11 (m, 2H), 4.02 (2s, 6H), 3.77 (m, 2H).

Example 109

2-Ethyl-4-(4-fluorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro[1,2,4]triazine-6-carboxylicacid [4-(6,7-diethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide. TFA saltOff-white solid; LCMS m/z=604 (M+1); ¹H NMR (DMSO) δ: 10.98 (s, 1H),8.74 (d, 1H, J=6.2 Hz), 8.03 (dd 1H, J=12.6, 2.2 Hz), 7.69 (s, 1H),7.66-7.54 (m, 2H), 7.51 (s, 1H), 7.46-7.34 (m, 4H), 6.89 (d, 1H, J=5.0Hz), 4.29 (m, 4H), 4.09 (q, 2H, J=7.1 Hz) 1.45 (overlapping triplets,6H), 1.35 (t, 3H, J=7.1 Hz).

Example 110

4-(4-Fluoro-phenyl)-2-isopropyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylicacid [5-(6,7-dimethoxy-quinolin-4-yloxy)-pyridin-2-yl]-amide di-TFAsalt. Off-white solid, LCMS m/z=573 (M+1); ¹H NMR DMSO) δ: 11.29 (s,1H), 8.75 (d, 1H, J=6.2 Hz), 8.50 (d, 1H, J=2.8 Hz), 8.42 (m, 1H), 7.99(dd, 1H, J=9, 2.9 Hz), 7.70 (s, 1H), 7.51 (s, 1H), 7.45-7.37 (m, 4H),6.93 (d, 1H, J=6.1 Hz), 4.91 (m, 1H), 4.02 (s, 3H), 4.01 (s, 3H), 1.38(d, J=6.6 Hz).

Example 111

3-Fluoro-4-(7-methoxy-quinolin-4-yloxy)-phenylamine; hydrochloride

Step a. A mixture of 4-chloro-7-methoxyquinoline (1.0 g mg, 5 mmol),(3-fluoro-4-hydroxyphenyl)-carbamic acid t-butyl ester (1.88 mg, 8.26mmol) and 4-dimethylaminopyridine (1010 mg, 8.26 mmol) inN,N-dimethylformamide (25 mL) was stirred at 145° C. for 5 h. Themixture was cooled to rt, the solvent was removed and the residue wastaken in DCM and washed with water and brine. After drying, the solventwas evaporated. The crude product was purified by flash chromatography(hexanes:EtOAc 1:1) to give a white solid; LCMS=385 (M+1).

Step b. The intermediate from step-a was treated with 4M HCl in dioxane(4 mL, 50 mmol) and the mixture was stirred at rt overnight. The solventwas removed and the mixture was triturated with ether and dried to 368mg (20%, two steps) of3-fluoro-4-(7-methoxy-quinolin-4-yloxy)-phenylamine; hydrochloride. LCMSm/z=285 (M+1); ¹H NMR (DMSO) δ: 8.98 (d, 1H, J=6.6 Hz), 8.50 (d, 1H,J=9.3 Hz), 7.78 (d, 1H, J=2.4 Hz), 7.42 (t, 1H), 7.61 (m, 1H), 7.04-6.84(m, 4H), 4.03 (s, 3H), 3.72 (s, 3H).

Step c.4-(4-Fluorophenyl)-2-isopropyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylicacid [3-fluoro-4-(7-methoxyquinolin-4-yloxy)-phenyl]-amide TFA salt.This compound was synthesized from3-fluoro-4-(7-methoxy-quinolin-4-yloxy)-phenylamine hydrochloride and4-(4-fluorophenyl)-2-isopropyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylicacid using the procedure for example 103 to give a white solid, LCMSm/z=560 (M+1); ¹H NMR (DMSO) δ: 10.98 (s, 1H), 8.88 (d, 1H, J=6.1 Hz),8.43 (d, 1H, J=9.8 Hz), 8.04 (dd, 1H, J=12.6, 2.2 Hz), 7.63-7.34 (m,8H), 6.88 (d, 1H, J=6.0 Hz), 4.90 (m, 1H), 1.38 (d, 6H, J=6.6 Hz).

Example 112

4-(4-Fluorophenyl)-3,5-dioxo-2-(2-oxo-propyl)-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylicacid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide. TFA saltoff-white solid, LCMS m/z=604 (M+1); ¹H NMR (DMSO) δ: 11.04 (s, 1H),8.78 (d, 1H, J=6.3 Hz), 8.02 (dd 1H, J=11.5, 2.1 Hz), 7.73 (s, 1H), 7.62(m, 2H), 7.55 (s, 1H), 7.39-7.34 (m, 4H), 6.94 (d, 1H, J=6.2 Hz), 4.02(2s, 6H), 2.25 (s, 3H).

Example 113

4-(4-Fluoro-phenyl)-3,5-dioxo-2-prop-2-ynyl-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide TFAsalt. A mixture of example 107 (25 mg, 0.046 mmol), propargyl bromide(10 uL, 0.1 mmol), and potassium carbonate (10 mg, 0.07 mmol) inN,N-dimethylformamide (1 mL) was stirred at rt 18 h. The mixture wasfiltered, solvent was removed and the product was purified by reversephase HPLC to give an off-white solid (7 mg, 30%). LCMS m/z=586 (M+1);¹H NMR (DMSO) δ: 10.99 (s, 1H), 8.71 (d, 1H, J=6.1 Hz), 8.0 (dd, 1H,J=2.3, 12.7 Hz), 7.68 (s, 1H), 7.65-7.58 (m, 2H), 7.4 (s, 1H), 7.37-7.35(m, 4H), 6.84 (d, 1H, J=5.8 Hz), 4.88 (d, 2H, J=2.3 Hz), 4.01 (2s, 6H),3.53 (s, 3H).

Example 114

2-Methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylic acid[4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide. TFA salt. Amixture of2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid(500 mg, 3 mmol) (Yuen, K. J Org. Chem. 1962, 27, 976),4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenylamine (0.80 g, 2.54mmol) and N,N,N′,N-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (1.06 g, 2.80 mmol) and N,N-diisopropylethylamine(1.33 mL, 7.64 mmol) in N,N-dimethylformamide (8 mL) was stirred at rt18 h. The solvent was removed and the residue was triturated with DCMcollected and dried. Yield-quantitative, LCMS m/z=468 (M+1); ¹H NMR(DMSO) δ: 12.69 (br s, 1H), 11.01 (s, 1H), 8.77 (d, 1H, J=6.2 Hz), 8.01(dd, 1H, J=2.2, 11.4 Hz), 7.72 (s, 1H), 7.64-7.57 (m, 2H), 7.56 (s, 1H),6.92 (d, 1H, J=5.6 Hz), 4.03 (2s, 6H), 3.58 (s, 3H).

Example 115

2-Methyl-3,5-dioxo-4-prop-2-ynyl-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylicacid [4-(6,7-dimethoxy-uinolin-4-yloxy)-3-fluoro-phenyl]-amide. TFAsalt. A mixture of example 114 (100 mg, 0.2 mmol), propargyl bromide (60uL, 0.7 mmol), and potassium carbonate (44.4 mg, 0.321 mmol) inN,N-dimethylformamide (3 mL) was stirred at rt 18 h.

The mixture was filtered and the solvent was removed. The product waspurified by reverse phase HPLC to give an off-white solid (36 mg, 30%).LCMS m/z=506 (M+1); ¹H NMR (DMSO) δ: 10.98 (s, 1H), 8.79 (d, 1H, J=6.2Hz), 8.00 (dd, 1H, J=2.3, 12.5 Hz), 7.72 (s, 1H), 7.66-7.58 (m, 2H),7.53 (s, 1H), 6.92 (d, 1H, J=6.1 Hz), 4.61 (d, 2H, J=2.4 Hz), 4.03 (2s,6H), 3.65 (s, 3H), 3.29 (t, 1H, J=2.4 Hz).

The following examples were synthesized from Example 114 using theprocedure for Example 115.

Example 116

2-Methyl-4-(5-methyl-isoxazol-3-ylmethyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide. TFAsalt. Off-white solid; LCMS m/z=563 (M+1); ¹H NMR (DMSO) δ: 10.99 (s,1H), 8.76 (d, J=6.2 Hz, 1H), 8.0 (dd, 1H, J=2.2, 12.6 Hz), 7.71 (s, 1H),7.66-7.53 (m, 2H), 7.71 (s, 1H), 6.80 (d, 1H, J=6.0 Hz), 6.27 (s, 1H),5.05 (s, 2H), 4.02 (2xs, 6H), 3.66 (s, 3H), 2.38 (s, 3H).

Example 117

2-Methyl-3,5-dioxo-4-pent-2-ynyl-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylicacid [4-(6,7-dimethoxy-uinolin-4-yloxy)-3-fluoro-phenyl]-amide. TFAsalt. yellowish solid. LCMS m/z=534 (M+1); ¹H NMR (DMSO) δ: 10.98 (s,1H), 8.75 (d, 1H, J=6.2 Hz), 8.00 (dd, 1H, J=2.3, 12.5 Hz), 7.71 (s,1H), 7.66-7.57 (m, 2H), 7.53 (s, 1H), 6.89 (d, 1H, J=6.0 Hz), 4.56 (s,2H), 4.02 (2s, 6H), 3.65 (s, 3H), 2.18 (m, 2H), 1.04 (t, 3H, J=7.5 Hz).

Example 118

4-(4-Hydroxy-but-2-ynyl)-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide. TFAsalt Off-white solid; LCMS m/z=536 (M+1); ¹H NMR (DMSO) δ: 10.98 (s,1H), 8.74 (d, J=6.1 Hz, 1H), 7.99 (dd, 1H, J=2.1, 12.7 Hz), 7.70 (s,1H), 7.65-7.54 (m, 2H), 7.51 (s, 1H), 6.87 (d, 1H, J=5.9 Hz), 4.65 (s,2H), 4.07 (s, 2H), 4.02 (2xs, 6H), 3.65 (s, 2H).

Example 119

4-(1,5-Dimethyl-1H-pyrazol-3-ylmethyl)-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylicacid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide. TFA saltOff-white solid; LCMS m/z=576 (M+1); ¹H NMR (DMSO) δ: 11.00 (s, 1H),8.81 (d, 1H, J=6.3 Hz), 8.01 (d, 1H, 11.2 Hz), 7.74 (s, 1H), 7.65-7.59(s, m, 3H), 6.96 (d, 1H, J=5.9 Hz), 6.02 (s, 1H), 5.01 (s, 2H), 4.04 (s,6H), 3.84 (s, 3H), 3.65 (s, 3H), 2.07 (s, 3H). 13.30 (s, 1H), 10.97 (s,1H), 8.71 (d, 1H, J=6.0 Hz), 8.02 (dd, 1H, J=12.7, 2.3 Hz), 7.68 (s,1H), 7.65 (m, 1H), 7.65 (m, 1H), 7.56 (m, 1H), 7.5 (s, 1H), 7.46-7.31 (2m, 4H), 6.83 (d, 1H, J=6.3 Hz), 4.01 (s, 6H).

Example 120

2-Methyl-3,5-dioxo-4-(2-pyrazol-1-yl-ethyl)-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylicacid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide. TFA saltOff-white solid. LCMS m/z=562 (M+1); ¹H NMR (DMSO) δ: 10.98 (s, 1H),8.77 (d, 1H, J=6.0 Hz), 8.01 (dd, 1H, J=2.2, 12.6 Hz), 7.77 (d, 1H,J=2.0 Hz), 7.72 (s, 2H), 7.66-7.57 (m, 2H), 7.55 (s, 1H), 7.42 (d, 1H,J=1.4 Hz), 6.90 (d, 1H, J=6.0 Hz)), 6.22 (d, 1H, J=1.9 Hz), 4.39 (m,2H), 4.22 (m, 2H), 4.03 (2s, 6H), 3.61 (s, 3H).

Example 121

2-Methyl-4-(1-methyl-1H-[1,2,4]triazol-3-ylmethyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide TFA saltOff-white solid; LCMS m/z=563 (M+1); ¹H NMR (DMSO) δ: 11.06 (s, 1H),8.78 (d, 1H, J=6.3 Hz), 8.39 (s, 1H), 7.99 (dd, 1H, J=2.3, 12.5 Hz),7.93 (s, 1H), 7.68-7.58 (m, 2H), 7.73 (s, 1H), 6.93 (d, 1H, J=6.2 Hz),5.06 (s, 2H), 4.03 (s, 3H), 4.02 (s, 3H), 3.81 (s, 3H), 3.66 (s, 3H).

Example 122

4-Cyanomethyl-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide. TFAsalt; LCMS m/z=507 (M+1); ¹H NMR (DMSO) δ: 10.95 (s, 1H), 8.76 (d, 1H,J=6.2 Hz), 7.81 (dd, 1H, J=2.2, 12.6 Hz), 7.72 (s, 1H), 7.68-7.58 (m,2H), 7.56 (s, 1H), 4.92 (s, 2H), 4.03 (s, 3H), 4.02 (s, 3H), 3.66 (s,3H).

Example 123

4-Ethyl-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylicacid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluoro-phenyl]-amide TFA salt.LCMS m/z=496 (M+1); ¹H NMR (DMSO) δ: 11.03 ((s, 1H), 8.78 (d, 1H, J=6.2Hz), 8.04 (dd, 1H, J=2.2, 12.6 Hz), 7.72 (s, 1H), 7.67-7.58 (m, 2H),7.55 (s, 1H), 6.92 (d, 1H, J=6.2 Hz), 4.03 (s, 6H), 3.89 (q, 2H, J=7.1Hz), 3.64 (s, 3H), 1.18 (t, 3H, J=7.1 Hz).

Example 124

4-Allyl-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide TFAsalt. LCMS m/z=508 (M+1); ¹H NMR DMSO) δ: 11.00 (s, 1H), 8.76 (d, 1H,J=6.2 Hz), 8.02 (dd, 1H, J=2.0, 12.6 Hz), 7.72 (s, 1H), 7.67-7.57 (m,2H), 7.53 (s, 1H), 6.90 (d, 1H, J=6.0 Hz), 5.84 (m, 1H), 5.23 (ddd, 2H,J=25.8, 7.2 and 1.4 Hz), 4.46 (d, 1H, J=4.3 Hz), 4.03 (2s, 6H), 3.65 (s,3H).

Example 125

4-Cyclopropylmethyl-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide TFAsalt. LCMS m/z=522 (M+1); ¹H NMR (DMSO) δ: 11.01 (s, 1H), 8.74 (d, 1H,J=6.1 Hz), 8.01 (m, 1H), 7.70 (s, 1H), 7.65-7.59 (m, 2H), 7.53 (s, 1H),6.87 (d, 1H, J=6.0 Hz), 4.02 (2s, 6H), 3.92 (m, 1H), 3.75 (d, 1H, J=7.0Hz), 3.64 (s, 3H), 2.36 (m, 2H), 1.18 (m, 1H), 0.49 (m, 1H), 0.38 (m,1H).

Example 126

2-Methyl-3,5-dioxo-4-(tetrahydro-pyran-4-ylmethyl)-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide TFA saltLCMS m/z=566 (M+1); ¹H NMR (DMSO) δ: 10.99 (s, 1H), 8.75 (d, 1H, J=6.1Hz), 8.01 (dd, 1H, J=12.6, 2.3 Hz), 7.71 (s, 1H), 7.65-7.57 (m, 2H),7.52 (s, 1H), 6.88 (d, 1H, J=6.1 Hz), 4.02 (2s, 6H), 3.84 (m, 2H), 3.76(d, 2H, J=7.0 Hz), 3.64 (s, 3H), 3.24 (m, 3H), 2.02 (m, 1H), 1.57 (m,2H), 1.27 (m, 2H).

Example 127

4-Isobutyl-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide TFAsalt. LCMS m/z=524 (M+1); ¹H NMR (DMSO) δ: 11.02 (s, 1H), 8.76 (d, 1H,J=6.2 Hz), 8.01 (dd, 1H, J=2.3, 12.6 Hz), 7.71 (s, 1H), 7.66-7.57 (m,2H), 7.53 (s, 1H), 6.90 (d, 1H, J=5.9 Hz), 4.03 (2s, 6H), 3.70 (d, 2H,J=7.3 Hz), 3.64 (s, 3H), 2.07 (m, 1H), 0.90 (d, 6H, J=6.7 Hz).

Example 128

4-Cyclobutylmethyl-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide. TFAsalt. LCMS m/z=536 (M+1); ¹H NMR (DMSO) δ: 11.02 (s, 1H), 8.79 (d, 1H,J=6.3 Hz), 8.01 (dd, 1H, J=2.2, 12.4 Hz), 7.74 (s, 1H), 7.69-7.58 (m,2H), 7.55 (s, 1H), 6.95 (d, 1H, J=6.2 Hz), 4.03 (s, 6H), 3.92 (d, 2H,J=7.0 Hz), 3.63 (s, 3H), 2.66 (m, 1H), 1.99 (m, 2H), 1.81 (m, 4H).

Example 129

4-(2,2-Dimethylpropyl)-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylicacid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide TFA salt.LCMS m/z=538 (M+1); ¹H NMR (DMSO) δ: 11.0 (s, 1H), 8.72 (d, 1H, J=6.0Hz), 7.99 (dd, 1H, J=2.2, 12.5 Hz), 7.69 (s, 1H), 7.63-7.55 (m, 2H),7.50 (s, 1H), 6.83 (d, 1H, J=5.8 Hz), 4.01 (2s, 6H), 3.63 (s, 3H), 0.94(s, 9H).

Example 130

2-Methyl-4-(2-methyl-butyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide TFAsalt. LCMS m/z=538 (M+1); ¹H NMR (DMSO) δ: 11.01 (s, 1H), 8.76 (d, 1H,J=6.2 Hz), 8.01 (dd, 1H, J=2.2, 12.6 Hz), 7.71 (s, 1H), 7.66-7.57 (m,2H), 7.53 (s, 1H), 6.89 (d, 1H, J=6.1 Hz), 4.03 (2s, 6H), 3.76 (m, 2H),3.64 (s, 3H), 1.87 (m, 1H), 1.40 (m, 1H), 1.17 (m, 1H), 0.87 (m, 6H).

Example 131

3-(4-Fluoro-phenyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid [4-([1,3]dioxolo[4,5-g]quinolin-8-yloxy)-3-fluoro-phenyl]-amide,TFA salt. This compound was synthesized from3-(4-fluorophenyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid and 4-(1,3-dioxolo[4,5-g]quinolin-8-yloxy)-3-fluoro-phenylaminehydrochloride (LCMS m/z=299 (M+1); ¹H NMR (DMSO) δ: 8.80 (d, 1H, J=6.6Hz), 7.85 (s, 1H), 7.74 (s, 1H), 7.31 (t, 1H, J=8.9 Hz), 6.94 (dd, 1H,J=6.6, 0.8 Hz), 6.87 (dd, 1H, J=12.6, 2.2 Hz), 6.76 (d, 1H, J=12.6, 2.1Hz), 6.43 (s, 2H); synthesized using the procedure for example 111 stepsa-b)) using the procedure for examples 103. LCMS m/z=545 (M+1); ¹H NMR(DMSO) δ: 11.08 (s, 1H), 8.89 (s, 1H), 8.69 (d, 1H, J=6.0 Hz), 8.43 (d,1H, J=9.8 Hz), 8.05 (dd, 1H, J=12.8, 2.4 Hz), 7.76 (s, 1H), 7.68-7.52 (2m and a s, 3H), 7.48-7.31 (m, 4H), 6.84 (d, 1H, J=5.9 Hz), 6.36 (s, 2H),3.54 (s, 3H).

Example 132

1-Ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid[4-(2,3-dihydro-[1,4]dioxino[2,3-g]quinolin-9-yloxy)-3-fluoro-phenyl]-amideTFA salt. This compound was synthesized from1-ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid and4-(2,3-dihydro-[1,4]dioxino[2,3-g]quinolin-9-yloxy)-3-fluorophenylamineusing the procedure for examples 103. LCMS m/z=545 (M+1); ¹H NMR (DMSO)δ: 11.09 (s, 1H), 8.89 (s, 1H), 8.78 (d, 1H, J=6.2 Hz), 8.43 (d, 1H,J=9.8 Hz), 8.07 (dd, 1H, J=12.8, 2.2 Hz), 7.83 (s, 1H), 7.62-7.50 (2 mand a s, 3H), 7.44-7.32 (2m, 4H), 6.85 (d, 1H, J=6.1 Hz), 4.49 (m, 4H),4.02 (q, 2H, J=7.0 Hz), 1.30 (t, 3H, J=7.0 Hz).

Example 133

2-Cyclopropylmethyl-4-(4-fluorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide TFAsalt. This compound was synthesized from1-cyclopropylmethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid and 4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenylamine using theprocedure for example 103. LCMS m/z=602 (M+1); ¹H NMR (DMSO) δ: 10.98(s, 1H), 8.72 (d, 1H, J=5.9 Hz), 8.02 (dd 1H, J=12.6, 2.2 Hz), 7.69 (s,1H), 7.66-7.56 (m, 2H), 7.50 (s, 1H), 7.45-7.36 (m and s, 4H), 7.27 (m,1H), 6.85 (d, 1H, J=5.1 Hz), 5.12 (m, 1H), 4.02 (m and 2s, 7H), 2.49 (m,1H), 2.32 (m, 2H), 1.80 (m, 2H).

Example 134

Step a. 4-Chloro-6,7-dimethoxyquinoline (0.40 g, 1.79 mmol,p-nitroaniline (0.414 g, 2.68 mmol) and p-toluenesulfonic acid (0.154 g,0.894 mmol) in 1-methoxy-2-propanol (5 mL) were heated to 120° C. for 8h. The mixture was cooled to rt, triturated with ether and filtered toyield (6,7-dimethoxyquinolin-4-yl)-(4-nitrophenyl)amine (0.43 g, 73%).LCMS m/z=326 (M+1); ¹H NMR (DMSO) δ: 14.37 (s, 1H), 10.72 (s, 1H), 8.54(d, 1H, J=6.80 Hz), 8.39 (d, 2H, J=9.08 Hz), 8.05 (s, 1H), 7.74 (d, 2H,J=9.09 Hz), 7.47 (d, 1H, 8.13 Hz), 7.43 (s, 1H), 7.19 (d, 1H, J=6.85),7.10 (d, 1H, J=7.84), 4.02 (d, 7H, J=5.48), 2.28, (s, 1H).

Step b. N-(6,7-Dimethoxyquinolin-4-yl)-benzene-1,4-diamine.(6,7-Dimethoxyquinolin-4-yl)-(4-nitrophenyl)amine (0.425 g, 1.31 mmol),palladium hydroxide (0.0844 g, 0.601 mmol) and potassium carbonate(0.542 g, 3.92 mmol) in methanol (106 mL) were hydrogenation on a Parrapparatus at 40 psi overnight. The mixture was filtered through Celiteand concentrated to yield a crude product which was purified by prep.HPLC to yield N-(6,7-dimethoxyquinolin-4-yl)-benzene-1,4-diamine (0.13g, 33%). LCMS m/z=296 (M+1).

Step c.1-Ethyl-3-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-ylamino)-phenyl]-amide1-Ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (0.104 g, 0.372 mmol), andN,N,N′,N-tetramethyl-O-(7-azabenzotriazol-1-yl)uraniumhexafluorophosphate (0.154 g, 0.406 mmol) in N,N-dimethylformamide (5mL) was added N,N-diisopropylethylamine (0.425 mL, 2.44 mmol). After 15min N-(6,7-dimethoxyquinolin-4-yl)-benzene-1,4-diamine (0.10 g, 0.34mmol) was added and stirred at rt for 18 h. The reaction mixture wasevaporated under vacuum, quenched with saturated NaHCO₃ solution andextracted with CH₂Cl₂. The combined organics were washed with brine,dried (Na₂SO₄), filtered and concentrated to obtain a crude productwhich was purified by prep. HPLC to give a brown solid (0.58 g, 31%).mp=178-181° C. (CHCl2, MeOH, ether and hexane); LCMS m/z=556 (M+H); ¹HNMR (DMSO-d6) δ: 10.85 (s, 1H), 8.85 (s, 1H), 8.65 (s, 1H), 8.25 (d, 1H,J=6.3 Hz), 7.70 (d, 2H, J=8.8 Hz), 7.65 (s, 2H), 7.45-7.29 (m, 7H), 7.23(s, 1H), 6.74 (d, 1H, J=5.3 Hz), 4.01 (d, 2H, J=7.1 Hz), 3.91 (d, 7H,J=10.6), 1.30 (t, 3H, J=7.1).

Example 135

3-(4-Fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid [4-(6,7-dimethoxyquinolin-4-ylamino)-phenyl]-amide. This compoundwas synthesized using N-(6,7-dimethoxyquinolin-4-yl)-benzene-1,4-diamineand3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid the method for example 134. mp=190-193° C.; LCMS m/z=570 (M+1); ¹HNMR (DMSO-d₆) δ: 10.85 (s, 1H), 8.65 (brs, 2H), 8.26 (d, 1H, J=5.3 Hz),7.71 (d, 2H, J=8.8 Hz), 7.65 (s, 1H), 7.27-7.47 (m, 7H), 7.23 (s, 1H),6.75 (d, 1H, J=5.3 Hz), 4.72-4.84 (m, 1H), 3.92 (s, 3H), 3.90 (s, 3H),1.42 (d, 7H, J=6.8 Hz).

Example 136

4-(4-Fluoro-phenyl)-2-isopropyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-ylamino)-phenyl]-amide. This compoundwas synthesized using N-(6,7-dimethoxyquinolin-4-yl)-benzene-1,4-diamineand4-(4-fluorophenyl)-2-isopropyl-3,5-dioxo-2,3,4,5-tetrahydro[1,2,4]triazine-6-carboxylicacid by the method for example 134. mp=152-155° C.; LCMS m/z=571 (M+1);¹H NMR (DMSO-d₆) δ: 8.67 (s, 1H), 7.68 (d, 2H, J=8.87 Hz), 7.54 (d, 2H,J=8.68 Hz), 7.20-7.34 (m, 12H), 7.10 (brs, 1H), 6.99 (s, 1H), 6.60 (d,2H, J=8.6 Hz), 4.04 (d, 7H, J=2.2 Hz), 3.79 (brs, 2H), 1.21 (t, 1H,J=7.0 Hz), 0.81-0.91 (m, 1H).

Example 137

Step a. 4-[(6,7-dimethoxy-4-quinolyl)sulfanyl]aniline.4-Chloro-6,7-dimethoxyquinoline (0.40 g, 1.79 mmol) and4-aminothiophenol (0.379 g, 2.68 mmol) in N,N-dimethylformamide (5 mL)was stirred at rt for 8 h. The product was extracted with calciumcarbonate, washed with brine, dried with sodium sulfate, filtered andconcentrated. The crude product was dissolved in CH₂Cl₂ and wasrecrystallized with ether and hexanes, and was filtered to yield4-[(6,7-dimethoxy-4-quinolyl)sulfanyl]aniline (0.49 g, 88%) as a yellowsolid. mp=235-238° C. LCMS m/z=313 (M+1); ¹H NMR (CDCl₃) δ: δ 8.58 (d,1H, J=6.41 Hz), 7.51 (s, 1H), 7.46 (s, ¹H), 7.31 (d, 2H, J=8.7 Hz), 6.81(d, 1H, J=6.1 Hz), 6.77 (d, 2H, J=8.6 Hz), 4.03 (d, 7H, J=5.6 Hz).

Step b.1-Ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-ylsulfanyl)-phenyl]-amide.1-Ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid and 4-(6,7-dimethoxyquinolin-4-ylsulfanyl)phenylamine were coupledusing the procedure for example 134 to produce1-ethyl-3-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-ylsulfanyl)-phenyl]-amide as a whitesolid, mp=241-244° C.; LCMS m/z=573 (M+1); ¹H NMR (DMSO-d₆) δ:11.04 (s,1H), 8.88 (s, 1H), 8.43 (d, 1H, J=4.8 Hz), 7.84 (d, 2H, J=8.72 Hz), 7.58(d, 2H, J=8.7 Hz), 7.30-7.44 (m, 6H), 6.64 (d, 1H, J=4.9 Hz), 4.01 (q,2H, J=7.05 Hz), 3.96 (q, 7H, J=6.4 Hz), 1.29 (t, 3H, J=7.1 Hz).

Example 138

3-(4-Fluoro-phenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-ylsulfanyl)-phenyl]-amide. Thiscompound was synthesized using the procedure for example 134 to give alight tan solid. mp=236-239° C.; LCMS m/z=587 (M+1); ¹H NMR (DMSO-d₆) a:11.04 (s, 1H), 8.67 (s, 1H), 8.44 (d, 1H, J=4.8 Hz), 7.84 (d, 2H, J=8.78Hz), 7.58 (d, 2H, J=8.7 Hz), 7.30-7.47 (m, 7H), 6.71 (d, 2H, J=4.9 Hz),4.72-4.81 (m, 1H), 3.92 (d, 7H, J=7.1 Hz), 1.42 (d, 7H, J=6.8).

Example 139

Step a. 4-Chloro-6,7-dimethoxyquinoline (0.50 g, 2.24 mmol),N-methyl(4-nitrophenyl)amine; (0.564 g, 3.35 mmol) and p-toluenesulfonicacid (0.192 g, 1.12 mmol) in 1-methoxy-2-propanol (6.56 mL, 67.1 mmol)were heated to 120° C. for 8 h. The reaction was cooled to rt,triturated with ether and filtered to yield(6,7-dimethoxyquinolin-4-yl)methyl(4-nitrophenyl)amine (0.40 g, 40%).LCMS m/z=340 (M+1); ¹H NMR (CDCl3) δ: 8.80 (d, 1H, J=4.8 Hz), 8.10 (d,2H, J=9.4 Hz), 7.5 (brs, 1H), 7.16 (d, 1H, J=4.8), 6.84 (s, 1H), 6.64(d, 2H, J=9.4 Hz), 4.05 (s, 3H), 3.81 (s, 3H), 3.52 (s, 3H).

Step b. (6,7-Dimethoxyquinolin-4-yl)-methyl-(4-nitrophenyl)amine (0.30g, 0.88 mmol), potassium carbonate (1.3 g, 9.4 mmol) and palladiumhydroxide (1.00 g, 7.12 mmol) was hydrogenated in a mixture of ethanol(32 mL, 540 mmol), N,N-dimethylformamide (5 mL, 60 mmol) and methylenechloride (19 mL, 290 mmol) at 40 psi overnight. The mixture was filteredthrough Celite, and washed with calcium carbonate solution and brinethen dried over sodium sulfate and concentrated to yield a crudeproduct. This material was purified by prep. HPLC to yield[N-(6,7-Dimethoxy-quinolin-4-yl)-N-methyl-benzene-1,4-diamine (0.180 g,66%). LCMS m/z=310 (M+1).

Step c.3-(4-Fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid {4-[(6,7-dimethoxy-quinolin-4-yl)-methyl-amino]-phenyl}-amide. Thiscompound was synthesized using3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid and N-(6,7-dimethoxyquinolin-4-yl)-N-methyl-benzene-1,4-diamine bythe method described for example 134. mp=224-227° C.; LCMS m/z=584(M+1); ¹H NMR (CDCl₃) δ: 10.66 (s, 1H), 8.65 (s, 1H), 8.64 (d, 1H, J=5.0Hz), 7.51 (d, 2H, J=9.0 Hz), 7.38 (s, 1H), 7.00 (d, 1H, J=5.8 Hz), 6.90(s, 1H), 6.86 (d, 2H, J=9.0 Hz), 4.90-5.00 (m, 1H), 4.00 (t, 3H), 3.63(t, 3H), 3.44 (t, 3H).

Example 140

1-Ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid {4-[(6,7-dimethoxy-quinolin-4-yl)-methylamino]-phenyl}-amide. Thiscompound was synthesized using1-ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid and N-(6,7-dimethoxyquinolin-4-yl)-N-methyl-benzene-1,4-diamine bythe method described for example 134. mp=199-202° C.; LCMS m/z=570(M+1); ¹H NMR (CDCl₃) δ: 10.62 (s, 1H), 8.64 (d, 1H, J=5.0 Hz), 8.60 (s,1H), 7.50 (d, 2H, J=9.0 Hz), 7.38 (s, 1H), 7.31 (s, 1H), 7.00 (d, 1H,J=5.3 Hz), 6.90 (s, 1H), 6.86 (d, 2H J=8.9 Hz), 4.01 (s, 1H), 4.00 (s,3H), 3.63 (s, 3H), 3.44 (s, 3H).

Example 141

Step a. 4-(6,7-Dimethoxy-quinazolin-4-yloxy)-phenylamine.4-Chloro-6,7-dimethoxy-quinazoline (0.500 g, 2.22 mmol), 4-aminophenol(0.291 g, 2.67 mmol), 2-butanone (4.01 mL, 44.5 mmol), 2N sodiumhydroxide solution (1.00 mL, 0.213 mmol), and tetra-N-butylammoniumbromide (0.308 g, 0.957 mmol) were combined and heated to reflux (80°C.) for 15 min. The reaction was cooled to rt. DCM was added and washedwith calcium carbonate solution and brine, then dried over sodiumsulfate and concentrated to yield a crude product. The solid wastriturated with diethyl ether and hexanes to yield4-(6,7-dimethoxyquinazolin-4-yloxy)-phenylamine (0.52 g, 78%). LCMSm/z=298 (M+1).

Step b.3-(4-Fluoro-phenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid [4-(6,7-dimethoxy-quinazolin-4-yloxy)-phenyl]-amide. This compoundwas synthesized using 4-(6,7-dimethoxyquinazolin-4-yloxy)-phenylamineand3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid by the procedure for example 134. mp=238-241° C.; LCMS m/z=572(M+1); ¹H NMR (CDCl₃) δ: 10.86 (s, 1H), 8.70 (s, 1H), 8.62 (s, 1H), 7.76(d, 2H, J=9.0 Hz), 7.54 (s, 1H), 7.32 (s, 1H), 4.90-5.03 (m, 1H), 4.06(t, 7H, J=20 Hz).

Example 142

1-Ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid [4-(6,7-dimethoxy-quinazolin-4-yloxy)-phenyl]-amide. This compoundwas synthesized using1-ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid and 4-(6,7-dimethoxy-quinazolin-4-yloxy)-phenylamine by theprocedure for example 134. mp=238-241° C.; LCMS m/z=558 (M+H); 1H NMR(CDCl3): δ 10.82 (s, 1H), 8.63 (d, 2H J=6.5 Hz), 7.76 (d, 2H, J=9.0 Hz),7.55 (s, 1H), 7.32 (s, 1H), 7.23 (d, 2H, J=8.9 Hz), 4.07 (s, 7H), 4.03(q, 3H, J=7.2 Hz), 1.59 (s, 1H), 1.49 (s, 1H), 1.46 (t, 3H, 7.2 Hz),1.20 (t, 1H, J=7.0 Hz), 1.03 (t, 1H, J=7.3 Hz).

Example 143

Step a. A solution of 4-chloro-6,7-dimethoxyquinoline (0.4 g, 2 mmol),3-methoxy-4-nitrophenol (0.30 g, 1.8 mmol), and 4-dimethylaminopyridine(0.011 g, 0.089 mmol) in chlorobenzene (5 mL) was stirred at 140° C.overnight. After cooling to rt the solid that formed was filtered anddried to yield pure product 0.48 g (75%), MS: 357 (M+H).

Step b. 6,7-Dimethoxy-4-(3-methoxy-4-nitrophenoxy)quinoline washydrogenated in EtOH/DMF using 10% Pd/C at 40 psi to yield4-(6,7-dimethoxyquinolin-4-yloxy)-2-methoxy-phenylamine. LCMS m/z=327(M+1); ¹H NMR (DMSO) δ: 8.43 (d, 1H, J=6 Hz), 7.5 (s, 1H), 7.37 (s, 1H),6.76 (d, 1H, J=2.6 Hz), 6.72 (d, 1H, J=9 Hz), 6.60 (dd, 1H, J=2.5, 8.5Hz), 6.41 (d, 1H, J=5.6 Hz), 3.75 (s, 3H), 3.31 (s, 6H).1-Ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-2-methoxyphenyl]-amide. Thiscompound was synthesized using4-(6,7-dimethoxyquinolin-4-yloxy)-2-methoxy-phenylamine and1-ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid using the procedure for example 1. LCMS m/z=587 (M+1); ¹H NMR(CDCl₃) δ: 11 (s, 1H), 8.63 (s, 1H), 8.54 (d, 1H, J=9 Hz), 8.49 (d, 1H,J=5 Hz), 7.55 (s, 1H), 7.42 (s, 1H), 7.26-7.23 (m, 3H), 6.82 (dd, 1H,J=3, 9 Hz), 6.74 (d, 1H, J=3 Hz), 6.52 (d, 1H, J=6 Hz), 4.05 (d, 6H),4.01 (q, 2H, J=8 Hz), 3.85 (s, 3H), 1.45 (t, 3H, J=8 Hz).

Example 144

1-Methyl-3-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-2-methoxy-phenyl]-amide. Thiscompound was synthesized using4-(6,7-dimethoxyquinolin-4-yloxy)-2-methoxy-phenylamine and3-(4-fluorophenyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid using the procedure for example 1. LCMS m/z=573 (M+1); ¹H NMR(CDCl₃) δ: 11 (s, 1H), 8.61 (s, 1H), 8.54 (d, 1H, J=9 Hz), 8.49 (d, 1H,J=5 Hz), 7.55 (s, 1H), 7.42 (s, 1H), 7.26-7.23 (m, 4H), 6.81 (dd, 1H,J=3, 9 Hz), 6.74 (d, 1H, J=3 Hz), 6.5 (d, 1H, J=5 Hz), 4.05 (s, 6H),3.84 (s, 3H), 3.61 (s, 3H).

Example 145

1-Isopropyl-3-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-2-methoxy-phenyl]-amide. Thiscompound was synthesized using4-(6,7-dimethoxyquinolin-4-yloxy)-2-methoxy-phenylamine and3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid using the procedure for example 1. LCMS m/z=601 (M+1); ¹H NMR(CDCl₃) δ: 11.0 (s, 1H), 8.68 (s, 1H), 8.54 (d, 1H J=9 Hz), 8.5 (d, 1H,J=6 Hz), 7.55 (s, 1H), 7.42 (s, 1H), 7.25-7.23 (m, 3H), 6.81 (dd, 1H,J=3.9 Hz), 6.74 (d, 1H, J=3 Hz), 6.52 (d, 1H, J=6 Hz), 4.96 (p, 1H, J=7Hz), 4.05 (d, 6H), 3.83 (s, 3H), 1.47 (d, 6H, J=6 Hz).

Example 146

Step a. Potassium tert-butoxide (0.13 g, 1.12 mmol) was added to4-amino-2-fluorophenol in dry N-methylpyrrolidinone (5 mL, 50 mmol) atrt and stirred for 30 min under an atmosphere of nitrogen. Then solid4-bromo-6,7-dimethoxyquinoline (0.30 g, 1.1 mmol) was added and thereaction stirred at 100° C. for 30 h. The mixture was concentrated,dissolved in EtOAc (˜75 mL), and washed 1× with 1N Na₂CO₃, water andNaCl solution, then dried over MgSO₄. The product was chromatographed onsilica gel (5% MeOH/DCM) to give4-(6,7-dimethoxyquinolin-4-yloxy)-2,3-difluoro-phenylamine 0.066 g(18%). LCMS m/z=333 (M+1). ¹H NMR (CDCl₃) δ: 8.5 (d, 1H, J=8 Hz), 7.58(s, 1H), 7.44 (s, 1H), 6.89-6.83 (m, 1H), 6.64-6.58 (m, 1H), 6.42 (d,1H, J=5 Hz), 4.05 (d, 6H, J=5 Hz).

Step b.1-Methyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-2,3-difluoro-phenyl]-amide.This compound was synthesized using4-(6,7-dimethoxyquinolin-4-yloxy)-2,3-difluoro-phenylamine and3-(4-fluorophenyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid using the procedure for example 1. mp=226-267° C.; LCMS m/z=579(M+1); ¹H NMR (CDCl₃) δ: 11.07 (s, 1H), 8.62 (s, 1H), 8.51 (d, 1H, J=6Hz), 8.25 (m, 1H), 7.55 (s, 1H), 7.43 (s, 1H), 7.25-7.23 (m, 4H), 7.05(m, 1H), 6.46 (d, 1H, J=5 Hz), 4.05 (d, 6H), 3.65 (s, 3H).

Example 147

1-Ethyl-3-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-2,3-difluoro-phenyl]-amide.This compound was synthesized using4-(6,7-dimethoxyquinolin-4-yloxy)-2,3-difluoro-phenylamine and1-ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid using the procedure for example 1. mp=270-272° C.; LCMS m/z=593(M+1); ¹H NMR (CDCl₃) δ: 11.08 (s, 1H), 8.63 (s, 1H), 5.51 (d, 1H, J=6Hz), 8.28-8.22 (m, 1H), 7.55 (s, 1H), 7.43 (s, 1H), 7.25-7.23 (m, 4H),7.09-7.03 (m, 1H), 6.46 (d, 1H, J=5 Hz), 4.05 (d, 6H), 4.04-3.99 (m,2H), 1.47 (t, 3H, J=8 Hz).

Example 148

Step a. 4-(6,7-Dimethoxy-quinolin-4-yloxy)-3-methylphenylamine wassynthesized using the procedure for example 143 steps a/b. LCMS m/z=311(M+1).

Step b.1-Ethyl-3-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-methyl-phenyl]-amide. Thiscompound was synthesized using4-(6,7-dimethoxy-quinolin-4-yloxy)-3-methylphenylamine and1-ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid using the procedure for example 1. mp=265-267° C.; LCMS m/z=571(M+1); ¹H NMR (DMSO-d6) δ: 10.93 (s, 1H), 8.85 (s, 1H), 8.44 (d, 1H, J=5Hz), 7.73 (dd, 1H, J=2, 8 Hz), 7.66 (d, 1H, J=3 Hz), 7.55 (s, 1H),7.46-7.33 (m, 5H), 7.18 (d, 1H, J=8 Hz), 6.31 (d, 1H, J=5 Hz), 4.02 (q,2H, J=8 Hz), 3.32 (s, 6H), 2.09 (s, 3H), 1.30 (t, 3H, J=8 Hz).

Example 149

3-(4-Fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-methyl-phenyl]-amide. Thiscompound was synthesized using4-(6,7-dimethoxy-quinolin-4-yloxy)-3-methylphenylamine and3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid using the procedure for example 1. mp=240-242° C.; LCMS m/z=543(M+1); ¹H NMR (CDCl₃) δ: 10.74 (s, 1H), 8.61 (s, 1H), 8.45 (d, 1H, J=5Hz), 7.63-7.61 (m, 1H), 7.60 (s, 1H), 7.58-7.53 (m, 1H), 7.44 (s, 1H),7.29-7.26 (m, 3H), 7.08 (d, 1H, J=10 Hz), 6.30 (d, 1H, J=5 Hz), 5.30 (s,1H), 4.05 (d, 6H, J=5 Hz), 2.05 (s, 3H).

Example 150

3-(4-Fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-methoxy-phenyl]-amide. Thiscompound was synthesized using4-(6,7-dimethoxy-quinolin-4-yloxy)-3-methoxy-phenylamine (LCMS m/z=327(M+1)) and3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid using the procedure for example 1. LCMS m/z=559 (M+1); ¹H NMR(CDCl₃) δ: 10.94 (s, 1H), 8.69 (s, 1H), 8.45 (d, 1H, J=6 Hz), 8.2 (d,1H, J=5 Hz), 7.61 (s, 1H), 7.42 (s, 1H), 7.32-7.26 (m, 3H), 7.2 (s, 1H),6.57 (d, 1H, J=7 Hz), 6.33 (d, 1H, J=7 Hz), 5.30 (s, 1H), 4.05 (s, 6H),3.76 (s, 3H).

Example 151

1-Ethyl-3-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-methoxy-phenyl]-amide. Thiscompound was synthesized using4-(6,7-dimethoxy-quinolin-4-yloxy)-3-methoxy-phenylamine and1-ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid using the procedure for example 1. mp=245-247° C.; LCMS m/z=587(M+1); ¹H NMR (DMSO-d6) δ: 10.98 (s, 1H), 8.89 (s, 1H), 8.46 (d, 1H, J=6Hz), 7.56 (d, 1H, J=2 Hz), 7.53 (s, 1H), 7.49 (dd, 1H, J=3, 9 Hz),7.45-7.41 (m, 2H), 7.39-7.34 (m, 3H), 7.25 (d, 1H, J=9 Hz), 6.36 (d, 1H,J=6 Hz), 4.01 (q, 2H, J=8 Hz), 3.95 (d, 6H), 3.71 (s, 3H), 1.3 (t, 3H,J=8 Hz).

Example 152

3-Chloro-4-(6,7-dimethoxy-quinolin-4-yloxy)-phenylamine was synthesizedusing the procedure for example 146 step a, LCMS=331 (M+1).1-Ethyl-3-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid[3-chloro-4-(6,7-dimethoxy-quinolin-4-yloxy)-3-methoxy-phenyl]-amide.This compound was synthesized using3-chloro-4-(6,7-dimethoxy-quinolin-4-yloxy)phenylamine and1-ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid using the procedure for example 1. mp=257-259° C.; LCMS m/z=591(M+1); ¹H NMR (DMSO-d6) δ: 11.0 (s, 1H), 8.88 (s, 1H), 8.47 (d, 1H, J=6Hz), 8.18 (d, 1H, J=3 Hz), 7.71 (dd, 1H, J=3, 9 Hz), 7.52 (s, 1H),7.45-7.33 (m, 6H), 6.37 (d, 1H, J=6 Hz), 4.0 (q, 2H, J=7 Hz), 3.95 (d,6H), 1.30 (t, 3H, J=7 Hz).

Example 153

[5-(6,7-Dimethoxy-quinolin-4-yloxy)-2-methyl-phenyl]-dimethyl-amine wassynthesized using the procedure for example 143 step a. LCMS m/z=340(M+1). ¹H NMR (CDCl₃) δ: 8.48 (d, 1H, J=9 Hz), 7.89 (s, 1H), 7.63 (s,1H), 6.83 (d, 1H, J=3 Hz), 6.80 (d, 1H, J=8 Hz), 6.74 (dd, 1H, J=3, 8.6Hz), 6.66 (d, 1H, J=5 Hz), 4.10 (d, 6H), 2.69 (s, 6H).1-Ethyl-3-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-2-dimethylamino-phenyl]-amide.This compound was synthesized using[5-(6,7-dimethoxyquinolin-4-yloxy)-2-methylphenyl]dimethylamine and1-ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid using the procedure for example 1. mp=144-145° C.; LCMS m/z=600(M+1); ¹H NMR (DMSO-d6) δ: 11.18 (s, 1H), 8.87 (s, 1H), 8.51 (d, 1H, J=9Hz), 8.47 (d, 1H, J=5 Hz), 7.51 (s, 1H), 7.45-7.33 (m, 5H), 7.10 (d, 1H,J=3 Hz), 6.98 (dd, 1H, J=3, 9 Hz), 6.49 (d, 1H, J=5 Hz), 4.01 (q, 2H,J=7 Hz), 3.94 (d, 6H), 2.58 (s, 6H), 1.29 (t, 3H, J=7 Hz).

Example 154

3-(4-Fluoro-phenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-2-dimethylamino-phenyl]-amide.This compound was synthesized using[5-(6,7-dimethoxyquinolin-4-yloxy)-2-methylphenyl]dimethylamine and3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid using the procedure for example 1. mp=231-233° C.; LCMS m/z=614(M+1); ¹H NMR (DMSO-d6) δ: 11.19 (s, 1H), 8.67 (s, 1H), 8.52-8.46 (m,2H), 7.50 (s, 1H), 7.45-7.33 (m, 5H), 7.11 (d, 1H, J=3 Hz), 6.97 (dd,1H, J=3, 9 Hz), 6.50 (d, 1H, J=5 Hz), 4.78 (p, 1H, J=6 Hz), 3.94 (d,6H), 2.58 (s, 6H), 1.42 (d, 6H, J=6 Hz).

Example 155

4-(6,7-Dimethoxy-quinolin-4-yloxy)-3-isopropyl-phenylamine wassynthesized using the procedure for example 143 step a. LCMS m/z=338(M+1); ¹H NMR (CDCl3) δ: 8.45 (d, 1H, J=7 Hz), 7.63 (s, 1H), 7.27 (s,1H), 6.88 (d, 1H, J=8.5 Hz), 6.73-6.71 (m, 1H), 6.63-6.58 (m, 1H), 6.44(d, 1H, J=6 Hz), 4.07 (s, 6H), 2.98-2.90 (m, 1H0, 1.16 (d, 6H, J=6 Hz).

1-Ethyl-3-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-isopropyl-phenyl]-amide. Thiscompound was synthesized using4-(6,7-dimethoxy-quinolin-4-yloxy)-3-isopropyl-phenylamine and1-ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid using the procedure for example 1. mp=173-175° C.; LCMS m/z=599(M+1); ¹H NMR (DMSO-d6) δ: 10.93 (s, 1H), 8.80 (s, 1H), 8.45 (d, 1H, J=6Hz), 7.76 (dd, 1H, J=2, 8 Hz), 7.68 (d, 1H, J=2 Hz), 7.55 (s, 1H),7.46-7.33 (m, 5H), 7.16 (d, 1H, J=8 Hz), 6.36 (d, 1H, J=5 Hz), 4.01 (q,2H, J=8 Hz), 3.94 (d, 6H), 2.99 (m, 1H), 1.3 (t, 3H, J=7 Hz), 1.14 (d,6H, J=7 Hz).

Example 156

3-(4-Fluoro-phenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-isopropyl-phenyl]-amide. Thiscompound was synthesized using4-(6,7-dimethoxy-quinolin-4-yloxy)-3-isopropyl-phenylamine and3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid using the procedure for example 1. mp=165-167° C.; LCMS m/z=613(M+1); ¹H NMR (CDCl₃) δ: 10.86 (s, 1H), 8.72 (s, 1H), 8.46 (d, 1H, J=5.5Hz), 7.66 (dd, 1H, J=2.5, 8 Hz), 7.63 (d, 1H, J=2 Hz), 7.60 (s, 1H),7.44 (s, 1H), 7.27-7.25 (m, 3H), 7.05 (d, 1H, J=9 Hz), 6.37 (d, 1H,J=5.5 Hz), 4.98 (p, 1H, J=8 Hz), 4.06 (s, 6H), 3.09 (p, 1H, J=8 Hz), 1.5(d, 6H, J=7 Hz), 1.18 (d, 6H, J=7 Hz).

Example 157

4-(6,7-Dimethoxy-quinolin-4-yloxy)-2,3-dimethyl-phenylamine wassynthesized using the procedure for example 143 step a. LCMS m/z=325(M+1).; ¹H NMR (CDCl₃) δ: 8.42 (d, 1H, J=7 Hz), 7.64 (s, 1H), 7.42 (s,1H), 6.83 (d, 1H, J=8 Hz), 6.65 (d, 1H, J=8 Hz), 6.26 (d, 1H, J=8 Hz),4.06 (d, 6H, J=4.5 Hz), 2.15 (s, 3H), 2.06 (s, 3H).1-Ethyl-3-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-2,3-dimethyl-phenyl]-amide.This compound was synthesized using4-(6,7-Dimethoxy-quinolin-4-yloxy)-2,3-dimethyl-phenylamine and1-ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid using the procedure for example 1. mp=283-285° C.; LCMS m/z=585(M+1); ¹H NMR (DMSO-d6) δ: 10.81 (s, 1H), 8.88 (s, 1H), 8.43 (d, 1H,J=5.5 Hz), 8.07 (d, 1H, J=8.5 Hz), 7.56 (s, 1H), 7.46-7.42 (m, 2H), 7.40(s, 1H), 7.39-7.33 (m, 2H), 7.10 (d, 1H, J=9 Hz), 6.26 (d, 1H, J=6 Hz),4.02 (q, 2H, J=7 Hz), 3.95 (s, 6H), 2.21 (s, 3H), 2.07 (s, 3H), 1.3 (t,3H, J=7 Hz).

Example 158

3-(4-Fluoro-phenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-2,3-dimethyl-phenyl]-amide.This compound was synthesized using4-(6,7-Dimethoxy-quinolin-4-yloxy)-2,3-dimethyl-phenylamine and3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid using the procedure for example 1. mp=238-240° C.; LCMS m/z=599(M+1); ¹H NMR (DMSO-d6) a: 10.82 (s, 1H), 8.68 (s, 1H), 8.43 (d, 1H,J=5.5 Hz), 8.06 (d, 1H, J=9 Hz), 7.56 (s, 1H), 7.47-7.42 (m, 2H),7.39-7.34 (m, 2H), 7.09 (d, 1H, J=9 Hz), 6.27 (d, 1H, J=5.5 Hz), 4.78(p, 1H, J=8 Hz), 3.95 (s, 6H), 2.21 (s, 3H), 2.07 (s, 3H), 1.43 (d, 6H,J=6 Hz).

Example 159

3-(1,1-Difluoro-ethyl)-4-(6,7-dimethoxy-quinolin-4-yloxy)-phenylaminewas synthesized using the procedure for example 143 step a. LCMS m/z=365(M+1). ¹H NMR (CDCl₃) δ: 8.48 (d, 1H, J=6 Hz), 7.56 (s, 1H), 7.42 (s,1H), 7.06-7.01 (m, 2H) 6.90-6.86 (m, 1H), 6.41 (d, 1H, J=6 Hz), 4.05 (s,6H).1-Ethyl-3-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid[4-(6,7-dimethoxy-quinolin-4-yloxy)-3-trifluoromethyl-phenyl]-amide.This compound was synthesized using3-(1,1-difluoroethyl)-4-(6,7-dimethoxy-quinolin-4-yloxy)-phenylamine and1-ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid using the procedure for example 1. mp=260-262° C.; LCMS m/z=625(M+1); ¹H NMR (DMSO-d6) δ: 11.08 (s, 1H), 8.89 (s, 1H), 8.51 (d, 1H, J=5Hz), 8.37 (d, 1H, J=2.5 Hz), 7.45-7.41 (m, 5H), 7.36 (t, 2H, J=8.5 Hz),6.58 (d, 1H, J=6 Hz), 4.02 (q, 2H, J=7.5 Hz), 3.90 (d, 6H), 1.30 (t, 3H,J=8 Hz).

Example 160

3-(4-Fluoro-phenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid[4-(6,7-dimethoxy-quinolin-4-yloxy)-3-trifluoromethyl-phenyl]-amide.This compound was synthesized using3-(1,1-difluoroethyl)-4-(6,7-dimethoxy-quinolin-4-yloxy)-phenylamine and3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid using the procedure for example 1. mp=228-230° C.; LCMS m/z=639(M+1); ¹H NMR (DMSO-d6) δ: 11.08 (s, 1H), 8.89 (s, 1H), 8.51 (d, 1H, J=5Hz), 8.37 (d, 1H, J=2.5 Hz), 7.45-7.41 (m, 5H), 7.36 (t, 2H, J=8.5 Hz),6.58 (d, 1H, J=6 Hz), 4.02 (q, 2H, J=7.5 Hz), 3.90 (d, 6H), 1.30 (t, 6H,J=8 Hz).

Example 161

4-(6,7-Dimethoxy-quinolin-4-yloxy)-3,5-dimethyl-phenylamine wassynthesized using the procedure for example 143 step a. LCMS m/z=325(M+1). ¹H NMR (CDCl₃) δ:8.43 (d, 1H, J=8 Hz), 7.65 (s, 1H), 7.48 (s,1H), 6.48 (s, 2H), 6.26 (d, 1H, J=6 Hz), 4.07 (s, 6H), 2.03 (s, 6H).1-Ethyl-3-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3,5-dimethyl-phenyl]-amide.This compound was synthesized using4-(6,7-dimethoxy-quinolin-4-yloxy)-3,5-dimethyl-phenylamine and1-ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid using the procedure for example 1. mp=240-242° C.; LCMS m/z=585(M+1); ¹H NMR (DMSO-d6) δ: 10.90 (s, 1H), 8.84 (s, 1H), 8.41 (d, 1H, J=5Hz), 7.61 (s, 1H), 7.55 (s, 1H), 7.45-7.33 (m, 6H), 6.19 (d, 1H, J=6Hz), 4.01 (q, 2H, J=8 Hz), 3.95 (d, 6H, J=5 Hz), 2.07 (s, 6H), 1.30 (t,3H, J=7 Hz).

Example 162

3-(4-Fluoro-phenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3,5-dimethyl-phenyl]-amide.This compound was synthesized using4-(6,7-dimethoxy-quinolin-4-yloxy)-3,5-dimethyl-phenylamine and3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid using the procedure for example 1. mp=180-182° C.; LCMS m/z=599(M+1); ¹H NMR (DMSO-d6) δ: 10.89 (s, 1H), 8.65 (s, 1H), 8.41 (d, 1H, J=5Hz), 7.60 (s, 1H), 7.58 (s, 2H), 7.45-7.33 (m, 5H), 6.19 (d, 1H, J=7Hz), 4.18 (p, 1H, J=7 Hz), 3.95 (d, 6H, J=6 Hz), 2.05 (s, 6H), 1.45 (d,6H, J=7 Hz).

Example 163

4-(6,7-Dimethoxy-quinolin-4-yloxy)-3-methyl-phenylamine was synthesizedusing the procedure for example 143 step a. LCMS m/z=311 (M+1).3-(4-Fluoro-phenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-methyl-phenyl]-amide. Thiscompound was synthesized using4-(6,7-Dimethoxy-quinolin-4-yloxy)-3-methyl-phenylamine and3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid using the procedure for example 1. mp=238-240° C.; LCMS m/z=585(M+1); ¹H NMR (DMSO-d6) δ: 10.92 (s, 1H), 8.65 (s, 1H), 8.44 (d, 1H, J=6Hz), 7.73-7.67 (m, 2H), 7.55 (s, 1H), 7.45-7.41 (m, 2H), 7.39-7.34 (m,3H), 7.17 (d, 1H, J=8 Hz), 6.31 (d, 1H, J=4.5 Hz), 4.78 (p, 1H, J=6 Hz),3.95 (s, 6H), 2.09 (s, 3H), 1.43 (d, 6H, J=7 Hz).

Example 164

2-Ethyl-4-(4-fluoro-phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylicacid [5-(6,7-dimethoxy-quinolin-4-yloxy)-pyridin-2-yl]-amide Thiscompound was synthesized using5-(6,7-dimethoxyquinolin-4-yloxy)-pyridin-2-ylamine and2-ethyl-4-(4-fluorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylicacid using the procedure for example 1. mp=200-202° C.; LCMS m/z=585(M+1); ¹H NMR (CDCl₃) δ: 11.13 (s, 1H), 8.52 (d, 1H, J=5 Hz), 8.48 (d,1H, J=8.5 Hz), 8.27 (d, 1H, J=2.6 Hz), 7.60 (dd, 1H, J=2, 9 Hz), 7.52(s, 1H), 7.43 (s, 1H), 7.28-7.26 (m, 3H), 6.47 (d, 1H, J=4.3 Hz), 4.33(q, 2H, J=8.5 Hz), 4.05 (d, 6H), 1.51 (t, 3H, J=8 Hz).

Example 165

2-Ethyl-4-(4-fluoro-phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-isopropyl-phenyl]-amide. Thiscompound was synthesized using4-(6,7-dimethoxy-quinolin-4-yloxy)-3-isopropyl-phenylamine and2-ethyl-4-(4-fluorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylicacid using the procedure for example 1. mp=155-156° C.; LCMS m/z=600(M+1); ¹H NMR (CDCl₃) δ: 10.78 (s, 1H), 8.47 (d, 1H, J=5.5 Hz). 7.72 (s,1H), 7.66 (d, 1H, J=8 Hz), 7.59 (s, 1H), 7.43 (s, 1H), 7.31-7.24 (m,3H), 7.07 (d, 1H, J=9 Hz), 6.35 (d, 1H, J=6 Hz), 4.34 (q, 2H, J=7.3 Hz),4.05 (s, 6H), 3.11 (m, 1H), 1.58 (t, 3H, J=6 Hz), 1.19 (d, 6H, J=7 Hz).

Example 166

4-(4-Fluoro-phenyl)-2-isopropyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-2-methoxy-phenyl]-amide. Thiscompound was synthesized using4-(6,7-dimethoxyquinolin-4-yloxy)-2-methoxy-phenylamine and4-(4-Fluorophenyl)-2-isopropyl-3,5-dioxo-2,3,4,5-tetrahydro[1,2,4]triazine-6-carboxylicacid using the procedure for example 1. mp=216-218° C.; LCMS m/z=602(M+1); ¹H NMR (CDCl₃) δ: 11.02 (s, 1H), 8.66 (d, 1H, J=8.5 Hz), 8.50 (d,1H, J=5 Hz), 7.54 (s, 1H), 7.43 (s, 1H), 7.30-7.27 (m, 3H), 6.83 (dd,1H, J=3.5, 10 Hz), 6.75 (d, 1H, J=2.5 Hz), 6.53 (d, 1H, J=5 Hz), 5.09(m, 1H), 4.05 (s, 6H), 3.86 (s, 3H), 1.53 (d, 6H, J=6.5 Hz)

Example 167

1-Ethyl-3-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid [4-(5,6-dimethoxy-quinolin-4-yloxy)-phenyl]-amide. This compoundwas synthesized using 4-(5,6-dimethoxy-quinolin-4-yloxy)-phenylamine and1-ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid using the procedure for example 1. mp>250° C.; LCMS m/z=557 (M+1);1H NMR (DMSO) δ: 10.92 (s, 1H), 8.86 (s, 1H), 8.48 (m, 1H), 7.79 (m,2H), 7.49 (s, 1H), 7.35-7.42 (m, 5H), 7.24-7.27 (m, 2H), 6.49 (m, 1H),4.00 (m, 2H), 3.94 (s, 3H), 3.92 (s, 3H), 1.29 (m, 3H).

Example 168

1-Ethyl-3-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid [4-(6,8-dimethoxy-quinolin-4-yloxy)-phenyl]-amide. This compoundwas synthesized using 4-(6,8-dimethoxy-quinolin-4-yloxy)-phenylamine and1-ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid using the procedure for example 1. mp=127-9° C.; LCMS m/z=557(M+1); 1H NMR (DMSO) δ: 10.93 (s, 1H), 8.87 (s, 1H), 8.45 (d, 1H, J=5Hz), 7.79 (d, 2H, J=8.8 Hz), 7.41-7.45 (m, 2H), 7.33-7.37 (m, 2H),7.24-(d, 2H, J=8.8 Hz), 7.10 (d, 1H, J=2.3 Hz), 6.86 (d, 1H, J=2.3 Hz),6.61 (d, 1H, J=5 Hz), 4.01 (q, 2H, J=7 Hz), 3.94 (s, 3H), 3.89 (s, 3H),1.29 (t, 3H, J=7 Hz).

Example 169

2-Ethyl-4-(4-fluoro-phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylicacid[4-(6,7-dimethoxy-quinolin-4-yloxy)-3-trifluoromethyl-phenyl]-amide.This compound was synthesized using4-(6,7-dimethoxy-quinolin-4-yloxy)-3-trifluoromethyl-phenylamine and2-ethyl-4-(4-fluoro-phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylicacid using the procedure for example 1. mp=148-50° C.; LCMS m/z=626(M+1); ¹H NMR (DMSO): 10.95 (s, 1H), 8.52 (d, 1H), 8.32 (s, 1H), 8.04(m, 1H), 7.35-7.49 (m, 8H), 6.60 (m, 1H), 4.08 (q, 2H, J=7 Hz), 3.97 (s,3H), 3.89 (s, 3H), 1.35 (t, 3H, J=7 Hz).

Example 170

2-Ethyl-4-(4-fluoro-phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylicacid [4-(6,7-dimethoxy-quinolin-4-yloxy)-2-methoxy-phenyl]-amide. Thiscompound was synthesized using4-(6,7-dimethoxy-quinolin-4-yloxy)-2-methoxy-phenylamine and2-ethyl-4-(4-fluoro-phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylicacid using the procedure for example 1. mp=264-6° C.; LCMS m/z=588(M+1); ¹H NMR (DMSO): 11.00 (s, 1H), 8.47-8.52 (m, 2H), 7.51 (s, 1H),7.38-7.46 (m, 5H), 7.10 (m, 1H), 6.88 (m, 1H), 6.53 (d, 1H, J=5 Hz),4.10 (q, 2H, J=7 Hz), 3.94 (s, 3H), 3.93 (s, 3H), 3.84 (s, 3H), 1.35 (t,3H, J=7 Hz).

Example 171

2-Ethyl-4-(4-fluoro-phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylicacid [3-fluoro-4-(7-methoxy-quinolin-4-yloxy)-phenyl]-amide. Thiscompound was synthesized using3-fluoro-4-(7-methoxy-quinolin-4-yloxy)-phenylamine and2-ethyl-4-(4-fluoro-phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylicacid. LCMS m/z=546 (M+1); ¹H NMR (DMSO): 11.00 (s, 1H), 8.88 (m, 1H),8.01-8.05 (m, 1H), 7.58-7.67 (m, 2H), 7.52-7.55 (m, 2H), 7.36-7.45 (m,4H), 6.88 (m, 1H), 4.08 (q, 2H, J=7 Hz), 4.01 (s, 3H), 1.35 (t, 3H, J=7Hz).

VI. Biology

AXL Kinase Assay

The ability of compounds to inhibit the kinase activity of recombinanthuman baculovirus-expressed AXL was measured by homogeneous TRF (HTRF)using Cisbio's KinEASE™ assay system in white 384-well Optiplates. Assaybuffer contained 1 mM DTT, 2 mM MnCl₂, 2% DMSO, 50 nM supplementenzymatic buffer, and 1× enzymatic buffer. A 2× concentration oftyrosine kinase (TK) substrate-biotin/ATP mixture made in assay bufferwas added to plates at 10 μL/well using the Multidrop Combi (ThermoFisher Scientific, Waltham, Mass.). The final concentrations were 0.3 μmTK substrate-biotin, and 1.3 μm ATP. Compounds (100 nL), diluted in 100%DMSO on the Biomek FX, (Beckman Coulter, Inc., Brea, Calif.), weretransferred to the assay plates using the Biomek FX pintool (2.5% finalDMSO in assay). A 2× concentration (final=12 ng/mL) of GST-AXL (dilutedin assay buffer) was added to plates at 10 uL/well using the MultidropCombi. Plates were sealed, briefly shaken and incubated at 25° C. for 30minutes. A 4× stock of Streptavidin-XL665 (final=18.8 nM) and a 1:100diluted stock of TK antibody-cryptate were made in HTRF detection bufferand mixed together just prior to adding 20 μL/well on the MultidropCombi. Plates were sealed, briefly shaken and incubated at 25° C. for 1hour. The fluorescence of the resulting solution was measured using thePerkinElmer EnVision™ 2102 multi-label plate reader (PerkinElmer,Waltham, Mass.) with an excitation wavelength of 337 nm (laser) andemission wavelengths of 590 and 665 nm. Raw data was expressed as theratio of 665/590×10,000.

C-MET Kinase Assay

The cMET kinase assay was performed in 384-well Fluotrac™ 200 HiBasemicroplates using the HTRF KinEASE™ assay described above for AXL exceptthat the assay volume was reduced to half. Enzyme concentration was 8ng/mL of recombinant human baculovirus-expressed cMET while thesubstrate concentrations were 0.1 μM and 0.02 μM for the biotinylatedpeptide and ATP, respectively. Instead of the Multidrop Combi, theBioRAPTR® FRD microfluidic workstation (Beckman Coulter, Brea, Calif.)was utilized for reagent additions.

Data Analysis

Inhibition curves for compounds were generated by plotting percentcontrol activity versus log 10 of the concentration of compound. IC₅₀values were calculated by nonlinear regression using the sigmoidaldose-response (variable slope) equation in GraphPad Prism as follows:

y=bottom+(top−bottom)/(1+10(log IC ₅₀ −x)*Hill Slope)

where y is the % kinase activity at a given concentration of compound, xis the logarithm of the concentration of compound, bottom is the % ofcontrol kinase activity at the highest compound concentration tested,and top is the % of control kinase activity at the lowest compoundconcentration examined. The values for bottom and top were fixed at 0and 100, respectively.

Results

Biological data for Example compounds is presented in the followingTable 1. Unless otherwise specified in Table 1, IC₅₀ nanomolar valueranges designated as A, B, or C indicate the following ranges:

IC₅₀ <10 nM A; IC₅₀ 10 nM to 100 nM B; and IC₅₀ 101 nM to 1,000 nM C;.“NT” denotes not tested.

Unless otherwise specified, all values are an average of two or moredeterminations.

TABLE 1 AXL and c-MET Inhibition c-MET IC₅₀ Example AXL IC₅₀ nM nM 1 A A2 A A 3 A B 4 A B 5 A B 6 A A 7 A B 8 A B 9 A A 10 B B 11 A B 12 B B 13B B 14 A A 15 B B 16 A A 17 A A 18 A B 19 B B 20 A B 21 A B 22 A B 23 AA 24 A A 25 B C 26 A B 27 A B 28 A A 29 A B 30 A B 31 A B 32 A A 33 A B34 A B 35 B B 36 B B 37 B C 38 B NT 39 A NT 40 B B 41 C C 42 B B 43 B B44 B B 45 B B 46 B A 47 B B 48 C C 49 A A 50 A A 51 A A 52 A B 53 A A 54A B 55 A B 56 B B 57 A C 58 A B 59 B B 60 B C 61 A A 62 A A 63 A A 64 AB 65 A B 66 A A 67 A B 68 A A 69 A A 70 B B 71 A A 72 A B 73 A B 74 A B75 A NT 76 A NT 77 A B 78 A B 79 A B 80 B C 81 B B 82 A B 83 A B 84 B B85 A A 86 A B 87 A B 88 A B 89 B C 90 A B 91 A B 92 C NT 93 B B 94 B B95 B B 96 A B 97 B C 98 A B 99 C NT 100 A B 101 A B 102 A A 103 A B 104A A 105 A B 106 A B 107 A A 108 A A 109 B B 110 A B 111 A B 112 A B 113A A 114 B B 115 A B 116 B B 117 B C 118 C C 119 C NT 120 C B 121 C NT122 C NT 123 B C 124 B B 125 A B 126 A C 127 A B 128 A B 129 A B 130 A B131 A B 132 A B 133 B B 134 B C 135 B C 136 B C 137 B B 138 B B 139 C NT140 C NT 141 B B 142 A B 143 A A 144 A B 145 A B 146 A A 147 A A 148 B B149 A A 150 A B 151 A B 152 A B 153 C NT 154 B C 155 B B 156 B B 157 B C158 B C 159 A B 160 B C 161 B B 162 B B 163 B B 164 A B 165 B B 166 B C167 A NT 168 B NT 169 B A 170 A B 171 A A

In one embodiment, the invention provides a compound of Formula I or asalt thereof having an AXL IC₅₀ of less than 1 μM. In one embodiment,the invention provides a compound of Formula I or a salt thereof havingan AXL IC₅₀ of less than 100 nM. In one embodiment, the inventionprovides a compound of Formula I or a salt thereof having an AXL IC₅₀ ofless than 10 nM. In one embodiment, the invention provides theexemplified compounds of Formula I or salts thereof having AXL IC₅₀s ofless than 1 μM. In one embodiment, the invention provides theexemplified compounds of Formula I or salts thereof having AXL IC₅₀s ofless than 100 nM. In one embodiment, the invention provides theexemplified compounds of Formula I or salts thereof having AXL IC₅₀s ofless than 10 nM.

In one embodiment, the invention provides a compound of Formula I or asalt thereof having a c-Met IC₅₀ of less than 1 μM. In one embodiment,the invention provides a compound of Formula I or a salt thereof havinga c-Met IC₅₀ of less than 100 nM. In one embodiment, the inventionprovides a compound of Formula I or a salt thereof having a c-Met IC₅₀of less than 10 nM. In one embodiment, the invention provides theexemplified compounds of Formula I or salts thereof having c-Met IC₅₀sof less than 1 μM. In one embodiment, the invention provides theexemplified compounds of Formula I or salts thereof having c-Met IC₅₀sof less than 100 nM. In one embodiment, the invention provides theexemplified compounds of Formula I or salts thereof having c-Met IC₅₀sof less than 10 nM.

In one embodiment, the invention provides a compound of Formula I or asalt thereof having AXL and c-Met IC₅₀s of less than 1 μM. In oneembodiment, the invention provides a compound of Formula I or a saltthereof having AXL and c-Met IC₅₀s of less than 100 nM. In oneembodiment, the invention provides a compound of Formula I or a saltthereof having AXL and c-Met IC₅₀s of less than 10 nM. In oneembodiment, the invention provides the exemplified compounds of FormulaI or salts thereof having AXL and c-Met IC₅₀s of less than 1 μM. In oneembodiment, the invention provides the exemplified compounds of FormulaI or salts thereof having AXL and c-Met IC₅₀s of less than 100 nM. Inone embodiment, the invention provides the exemplified compounds ofFormula I or salts thereof having AXL and c-Met IC₅₀s of less than 10nM.

Additional preferred Embodiments of the present invention include:

1. A compound of the formula

wherein:

R_(a) is H, alkyl, halo, cyano, hydroxyl, amino, alkylamino,dialkylamino where the alkyl groups of dialkylamino may be the same ordifferent, carbamoyl, N-alkylcarbamoyl, N,N-dialkylcarbamoyl, where thealkyl groups of dialkylcarbamoyl may be the same or different,trihalomethyl, or R_(a) is OA;

R_(b) is H, alkyl, halo, cyano, hydroxyl, amino, alkylamino,dialkylamino where the alkyl groups of dialkylamino may be the same ordifferent, carbamoyl, N-alkylcarbamoyl, N,N-dialkylcarbamoyl, where thealkyl groups of dialkylcarbamoyl may be the same or different,trihalomethyl, or R_(b) is OB;

R_(c) is H, alkyl, halo, cyano, hydroxyl, amino, alkylamino,dialkylamino where the alkyl groups of dialkylamino may be the same ordifferent, carbamoyl, N-alkylcarbamoyl, N,N-dialkylcarbamoyl, where thealkyl groups of dialkylcarbamoyl may be the same or different,trihalomethyl, or R_(c) is OJ;

R_(d) is H, alkyl, halo, cyano, hydroxyl, amino, alkylamino,dialkylamino where the alkyl groups of dialkylamino may be the same ordifferent, carbamoyl, N-alkylcarbamoyl, N,N-dialkylcarbamoyl, where thealkyl groups of dialkylcarbamoyl may be the same or different,trihalomethyl, or R_(d) is OL;

where A, B, J and L, are, independently, H, alkyl, alkoxyalkyl,cycloalkyl, cycloalkoxyalkyl, heterocyclylalkyl,heterocyclylalkoxyalkyl, arylalkyl or arylalkoxyalkyl, or A and Btogether with the oxygen atoms to which they are attached form

D is O, S, SO, SO₂, C═O, C(H)OH, CH₂, NH or N-alkyl;

E is H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclyl or heteroarylalkyl, where theheteroaryl group of heteroarylalkyl may be substituted or unsubstituted;

G is H, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclyl, alkyl or cycloalkyl, cycloalkylalkyl, alkenyl or alkynyl,where alkyl, alkenyl or cycloalkyl may be substituted by one, two orthree groups selected from the group consisting of alkanoyl, cycloalkyl,alkenyl, alkynyl, halo, hydroxyl, alkoxy, alkoxycarbonyl, heterocyclyl,aryl, substituted aryl, aryloxy, arylalkoxy, amino, alkylamino,dialkylamino, where the alkyl groups of dialkylamino may be the same ordifferent, heteroaryl, carboxyl, oxo, carbamoyl, alkylcarbamoyl,dialkylcarbamoyl, where the alkyl groups of dialkylcarbamoyl may be thesame or different, and heterocycyclylcarbonyl;

W is CH or N;

X is C—R₄ or N, where R₄ is H, OH or alkyl, where the alkyl group may besubstituted by hydroxyl, alkoxy, alkylamino, or dialkyl amino, where thealkyl groups of dialkylamino may be the same or different;

Y is N, CH or C where C may be substituted with one of the groups R₁ orR₂; and

R₁ and R₂ are, independently, H, alkyl, cycloalkyl, halo, alkoxy,trihaloalkyl, amino, alkylamino, dialkylamino, where the alkyl groups ondialkylamino may be the same or different, or heterocyclyl; and

R₃ is H, or alkyl; or

-   -   a pharmaceutically acceptable salt thereof.        2. A compound according to preferred Embodiment 1 wherein W is        CH.        3. A compound according to preferred Embodiment 1 wherein W is        N.        4. A compound according to preferred Embodiment 1 of the formula

wherein:

-   -   A and B are, independently, H, alkyl, alkoxyalkyl, cycloalkyl,        cycloalkoxyalkyl, heterocyclylalkyl, heterocyclylalkoxyalkyl,        arylalkyl or arylalkoxyalkyl, or A and B together with the        oxygen atoms to which they are attached form

-   -   D is O, S, NH, or C═O;    -   E is H, alkyl, substituted alkyl, alkenyl, substituted alkenyl,        alkynyl, substituted alkynyl, cycloalkyl, aryl, substituted        aryl, heteroaryl, heterocyclyl, substituted heteroaryl, or        heteroarylalkyl, where the heteroaryl group of heteroarylalkyl        may be substituted or unsubstituted;    -   G is H, aryl, substituted aryl, heteroaryl, substituted        heteroaryl, heterocyclyl, alkyl or cycloalkyl, cycloalkylalkyl,        alkenyl or alkynyl, where alkyl, alkenyl or cycloalkyl may be        substituted by one, two or three groups selected from the group        consisting of alkanoyl, cycloalkyl, alkenyl, alkynyl, halo,        hydroxyl, alkoxy, alkoxycarbonyl, heterocyclyl, aryl,        substituted aryl, aryloxy, arylalkoxy, amino, alkylamino,        dialkylamino, where the alkyl groups of dialkylamino may be the        same or different, heteroaryl, carboxyl, oxo, carbamoyl,        alkylcarbamoyl, dialkylcarbamoyl, where the alkyl groups of        dialkylcarbamoyl may be the same or different, and        heterocycyclylcarbonyl;    -   X is C—R₄ or N, where R₄ is H or alkyl;    -   Y is N, CH or C where C may be substituted with one of the        groups R₁ or R₂; and    -   R₁ and R₂ are, independently, H, alkyl, halo, alkoxy,        trihaloalkyl, amino, alkylamino, dialkylamino, where the alkyl        groups on dialkylamino may be the same or different; or    -   a pharmaceutically acceptable salt thereof.        5. A compound according to preferred Embodiment 4 wherein A and        B are, independently, alkyl, heterocyclylalkyl or        heterocyclylalkoxyalkyl.        6. A compound according to preferred Embodiment 4 wherein A and        B are, independently, alkyl.        7. A compound according to preferred Embodiment 4 wherein D is        O, S or NH.        8. A compound according to preferred Embodiment 4 wherein D is        O.        9. A compound according to preferred Embodiment 4 wherein R₁ and        R₂ are, independently, halo, alkoxy, alkyl or H.        10. A compound according to preferred Embodiment 4 wherein R₁        and R₂ are, independently, halo or alkoxy.        11. A compound according to preferred Embodiment 4 wherein R₁        and R₂ are, independently, methoxy or fluoro.        12. A compound according to preferred Embodiment 4 wherein X is        N or CH.        13. A compound according to preferred Embodiment 4 wherein X is        CH.        14. A compound according to preferred Embodiment 4 wherein G is        alkyl where alkyl may be substituted by one, two or three groups        selected from the group consisting of alkanoyl, cycloalkyl,        alkenyl, alkynyl, halo, hydroxyl, alkoxy, alkoxycarbonyl,        heterocyclyl, aryl, substituted aryl, aryloxy, arylalkoxy,        amino, alkylamino, dialkylamino, where the alkyl groups of        dialkylamino may be the same or different, heteroaryl, carboxyl,        oxo, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, where the        alkyl groups of dialkylcarbamoyl may be the same or different,        and heterocycyclylcarbonyl.        15. A compound according to preferred Embodiment 4 wherein E is        aryl, substituted aryl or cycloalkyl.        16. A compound according to preferred Embodiment 4 wherein E is        substituted aryl.        17. A compound according to preferred Embodiment 4 wherein A and        B are, independently, alkyl; D is O, S or NH; R₁ and R₂ are,        independently, halo, alkoxy, alkyl or H; X is N or CH; G is        alkyl where alkyl may be substituted by one, two or three groups        selected from the group consisting of alkanoyl, cycloalkyl,        alkenyl, alkynyl, halo, hydroxyl, alkoxy, alkoxycarbonyl,        heterocyclyl, aryl, substituted aryl, aryloxy, arylalkoxy,        amino, alkylamino, dialkylamino, where the alkyl groups of        dialkylamino may be the same or different, heteroaryl, carboxyl,        oxo, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, where the        alkyl groups of dialkylcarbamoyl may be the same or different,        and heterocycyclylcarbonyl; and E is aryl, substituted aryl or        cycloalkyl.        18. A compound which is

-   1-Ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid    [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]amide;

-   3-(4-Fluorophenyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic    acid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluoro-phenyl]-amide;

-   3-(4-Fluorophenyl)-1-(2-methoxyethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic    acid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide;

-   1-(2-Ethoxyethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic    acid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide;

-   3-(4-Fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic    acid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide;

-   1-Cyclopropylmethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic    acid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide;

-   3-(4-Fluorophenyl)-1-(3-methoxypropyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic    acid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide;

-   3-(4-Fluorophenyl)-1-isobutyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic    acid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide;

-   1-Allyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic    acid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide;

-   1-(2-Benzyloxyethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic    acid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide;

-   3-(4-Fluorophenyl)-2,4-dioxo-1-propyl-1,2,3,4-tetrahydropyrimidine-5-carboxylic    acid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide;

-   3-(4-Fluorophenyl)-1-(2-isopropoxyethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic    acid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide;

-   1-(3-Benzyloxypropyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic    acid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluoro phenyl]-amide;

-   1-(3,3-Difluoro-allyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic    acid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide;

-   3-(4-Fluorophenyl)-1-(3-methyl-but-2-enyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic    acid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide;

-   3-(4-Fluorophenyl)-1-(2-morpholin-4-yl-ethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic    acid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluoro phenyl]-amide;

-   3-(4-Fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic    acid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide;

-   3-(4-Fluorophenyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic    acid [4-(6,7-dimethoxyquinolin-4-yloxy)-phenyl]-amide;

-   1-(2-Benzyloxyethyl)-3-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic    acid [4-(6,7-dimethoxyquinolin-4-yloxy)-phenyl]-amide;

-   1-(2-Dimethylaminoethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic    acid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide;

-   1-(3-Benzyloxypropyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic    acid [4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-amide;

-   1-(3-Benzyloxypropyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic    acid [4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]-amide;

-   3-(4-Fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic    acid [4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-amide;

-   3-(4-Fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic    acid [4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-amide;

-   3-Cyclohexyl-1-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic    acid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide;

-   3-(4-Fluorophenyl)-2,4-dioxo-1-(2-pyrrolidin-1-yl-ethyl)-1,2,3,4-tetrahydropyrimidine-5-carboxylic    acid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluoro phenyl]-amide;

-   3-(4-Fluorophenyl)-2,4-dioxo-1-(2-piperidin-1-yl-ethyl)-1,2,3,4-tetrahydropyrimidine-5-carboxylic    acid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide;

-   1-Ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic    acid [4-(6,7-dimethoxyquinolin-4-yloxy)-phenyl]-amide;

-   1-Cyclobutyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic    acid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide;

-   3-(4-Fluorophenyl)-2,4-dioxo-1-(tetrahydropyran-4-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylic    acid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluoro phenyl]-amide;

-   1-Ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic    acid [5-(6,7-dimethoxyquinolin-4-yloxy)-pyridin-2-yl]-amide was    synthesized starting with    5-(6,7-dimethoxyquinolin-4-yloxy)-pyridin-2-ylamine;

-   1-Ethyl-3-(4-fluorophenyl)-6-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic    acid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide;

-   1-Ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic    acid [4-(6,7-diethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide;

-   3-(4-Fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic    acid [5-(6,7-dimethoxyquinolin-4-yloxy)-pyridin-2-yl]-amide;

-   1-Cyclopropylmethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic    acid [5-(6,7-dimethoxyquinolin-4-yloxy)pyridin-2-yl]-amide;

-   3-(4-Fluorophenyl)-2,4-dioxo-1-pentyl-1,2,3,4-tetrahydropyrimidine-5-carboxylic    acid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide;

-   3-(4-Fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic    acid [4-(6,7-diethoxyquinolin-4-yloxy)-3-fluoro-phenyl]-amide;

-   3-(4-Fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic    acid [4-(5,7-dimethoxyquinolin-4-yloxy)phenyl]-amide;

-   1-Ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic    acid [4-(5,7-dimethoxyquinolin-4-yloxy)-phenyl]-amide;

-   1-Ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic    acid    [4-(7-benzyloxy-6-methoxyquinolin-4-yloxy)-3-fluorophenyl]-amide;

-   3-(4-Fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic    acid    [4-(7-benzyloxy-6-methoxyquinolin-4-yloxy)-3-fluorophenyl]-amide;

-   1-Ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic    acid [3-fluoro-4-(7-hydroxy-6-methoxyquinolin-4-yloxy)phenyl]-amide;

-   1-Ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic    acid    {3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)quinolin-4-yloxy]phenyl}-amide;

-   1-Ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic    acid    {3-fluoro-4-[6-methoxy-7-(2-methoxyethoxyl)quinolin-4-yloxy]-phenyl}-amide;

-   1-Ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic    acid    {3-fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]phenyl}-amide;

-   3-(4-Fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic    acid    [3-fluoro-4-(7-hydroxy-6-methoxyquinolin-4-yloxy)-phenyl]-amide;

-   3-(4-Fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic    acid    {3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]phenyl}-amide;

-   3-(4-Fluorophenyl)-1-(2-hydroxyethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic    acid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide;

-   3-(4-Fluorophenyl)-1-(3-hydroxypropyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic    acid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide;

-   3-(4-Fluorophenyl)-1-(3-hydroxypropyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-2-fluoro-phenyl]-amide;

-   3-(4-Fluorophenyl)-1-(3-hydroxypropyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic    acid [4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-amide;

-   3-(4-Fluorophenyl)-1-(2-hydroxyethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic    acid [4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-amide;

-   1-((S)-2,3-Dihydroxypropyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic    acid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide;

-   3-(4-Fluorophenyl)-1-(4-hydroxybutyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic    acid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide;

-   3-(4-Fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic    acid [4-(6-cyano-7-methoxy-quinolin-4-yloxy)-phenyl]-amide;

-   3-(4-fluoro-phenyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic    acid    {4-[(6,7-dimethoxy-quinolin-4-yl)-hydroxy-methyl]-3-fluoro-phenyl}-amide;

-   3-(4-fluoro-phenyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-ylmethyl)-3-fluoro-phenyl]-amide;

-   1-Ethyl-3-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic    acid    [3-cyclopropyl-4-(6,7-dimethoxy-quinolin-4-yloxy)-phenyl]-amide;

-   3-(4-Fluoro-phenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic    acid    [3-cyclopropyl-4-(6,7-dimethoxy-quinolin-4-yloxy)-phenyl]-amide;

-   3-(4-Fluoro-phenyl)-2,4-dioxo-1-prop-2-ynyl-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide;

-   3-(4-Fluoro-phenyl)-1-(2-imidazol-1-yl-ethyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide;

-   3-(4-Fluoro-phenyl)-2,4-dioxo-1-(2-pyrazol-1-yl-ethyl)-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide;

-   3-(4-Fluoro-phenyl)-2,4-dioxo-1-phenethyl-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide;

-   1-[2-(1,3-Dioxolan-2-yl-ethyl)]-3-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide;

-   1-Diethylcarbamoylmethyl-3-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide;

-   3-(4-Fluoro-phenyl)-1-(2-morpholin-4-yl-2-oxo-ethyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide;

-   3-(4-Fluoro-phenyl)-2,4-dioxo-1-[2-(2-oxo-pyrrolidin-1-yl)-ethyl]-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide;

-   1-(2-Fluoro-ethyl)-3-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide;

-   [5-[4-(6,7-Dimethoxy-quinolin-4-yloxy)-3-fluoro-phenylcarbamoyl]-3-(4-fluoro-phenyl)-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl]-acetic    acid tert-butyl ester;

-   [5-[4-(6,7-Dimethoxyquinolin-4-yloxy)-3-fluorophenylcarbamoyl]-3-(4-fluorophenyl)-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl]-acetic    acid;

-   3-(4-Fluoro-phenyl)-1-oxazol-2-ylmethyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide;

-   3-(4-Fluoro-phenyl)-2,4-dioxo-1-(tetrahydro-furan-2-ylmethyl)-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide;

-   3-(4-Fluoro-phenyl)-2,4-dioxo-1-(tetrahydro-pyran-4-ylmethyl)-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide;

-   3-(4-Fluoro-phenyl)-1-(2-methyl-thiazol-4-ylmethyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide;

-   1-Cyclopentyl-3-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide;

-   1-Benzyl-3-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide;

-   3-(4-Fluoro-phenyl)-1-[2-(2-fluoro-phenyl)-ethyl]-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide;

-   3-(4-Fluoro-phenyl)-1-[2-(4-fluoro-phenyl)-ethyl]-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide;

-   1-(2-Cyclohexyl-ethyl)-3-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide;

-   3-(4-Fluoro-phenyl)-2,4-dioxo-1-(3-phenyl-propyl)-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide;

-   3-(4-Fluoro-phenyl)-2,4-dioxo-1-(2-oxo-2-pyrrolidin-1-yl-ethyl)-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide;

-   1-Dimethylcarbamoylmethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluorophenyl]-amide;

-   1-(1-Dimethylcarbamoyl-2-oxo-propyl)-3-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide;

-   3-(4-Fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-2-fluoro-phenyl]-amide;

-   3-(4-Fluoro-phenyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-2-fluoro-phenyl]-amide;

-   1-Ethyl-3-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-2-fluoro-phenyl]-amide;

-   1-Allyl-3-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-2-fluoro-phenyl]-amide;

-   3-(4-Fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3,5-difluoro-phenyl]-amide;

-   1-Ethyl-3-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3,5-difluoro-phenyl]-amide;

-   3-Ethyl-1-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide;

-   1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluorophenyl]-amide;

-   1,3-Diethyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide;

-   1,3-Diisopropyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide;

-   1,3-Bis-cyclopropylmethyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide;

-   1,3-Diallyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide;

-   1,3-Bis-(3-methyl-but-2-enyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide;

-   2,4-Dioxo-1,3-di-prop-2-ynyl-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide;

-   2,4-Dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid    [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide;

-   1-Ethyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide;

-   1-Isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide;

-   3-(4-Fluoro-phenyl)-2,4-dioxo-1-propyl-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic    acid [4-(6,7-dimethoxy-quinoline-4-carbonyl)-3-fluoro-phenyl]-amide;

-   4-(4-Fluoro-phenyl)-2-isopropyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide;

-   4-(4-Fluorophenyl)-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide;

-   2-Ethyl-4-(4-fluoro-phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide;

-   4-(4-Fluorophenyl)-2-isopropyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylic    acid    [4-(2,3-dihydro-[1,4]dioxino[2,3-g]quinolin-9-yloxy)-3-fluorophenyl]-amide;

-   4-(4-Fluoro-phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide;

-   4-(4-Fluorophenyl)-2-(2-hydroxyethyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylic    acid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide;

-   2-Ethyl-4-(4-fluorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro[1,2,4]triazine-6-carboxylic    acid [4-(6,7-diethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide;

-   4-(4-Fluoro-phenyl)-2-isopropyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylic    acid [5-(6,7-dimethoxy-quinolin-4-yloxy)-pyridin-2-yl]-amide;

-   4-(4-Fluorophenyl)-2-isopropyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylic    acid [3-fluoro-4-(7-methoxyquinolin-4-yloxy)-phenyl]-amide;

-   4-(4-Fluorophenyl)-3,5-dioxo-2-(2-oxo-propyl)-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylic    acid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide;

-   4-(4-Fluoro-phenyl)-3,5-dioxo-2-prop-2-ynyl-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide;

-   2-Methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide;

-   2-Methyl-3,5-dioxo-4-prop-2-ynyl-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylic    acid [4-(6,7-dimethoxy-uinolin-4-yloxy)-3-fluoro-phenyl]-amide;

-   2-Methyl-4-(5-methyl-isoxazol-3-ylmethyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide;

-   2-Methyl-3,5-dioxo-4-pent-2-ynyl-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylic    acid [4-(6,7-dimethoxy-uinolin-4-yloxy)-3-fluoro-phenyl]-amide;

-   4-(4-Hydroxy-but-2-ynyl)-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide;

-   4-(1,5-Dimethyl-1H-pyrazol-3-ylmethyl)-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylic    acid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide;

-   2-Methyl-3,5-dioxo-4-(2-pyrazol-1-yl-ethyl)-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylic    acid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide;

-   2-Methyl-4-(1-methyl-1H-[1,2,4]triazol-3-ylmethyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide;

-   4-Cyanomethyl-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide;

-   4-Ethyl-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylic    acid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluoro-phenyl]-amide;

-   4-Allyl-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide;

-   4-Cyclopropylmethyl-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide;

-   2-Methyl-3,5-dioxo-4-(tetrahydro-pyran-4-ylmethyl)-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide;

-   4-Isobutyl-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide;

-   4-Cyclobutylmethyl-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide;

-   4-(2,2-Dimethylpropyl)-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylic    acid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide;

-   ±2-Methyl-4-(2-methyl-butyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide;

-   3-(4-Fluoro-phenyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic    acid    [4-([1,3]dioxolo[4,5-g]quinolin-8-yloxy)-3-fluoro-phenyl]-amide;

-   1-Ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic    acid    [4-(2,3-dihydro-[1,4]dioxino[2,3-g]quinolin-9-yloxy)-3-fluoro-phenyl]-amide;

-   2-Cyclopropylmethyl-4-(4-fluorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide;

-   1-Ethyl-3-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-ylamino)-phenyl]-amide;

-   3-(4-Fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic    acid [4-(6,7-dimethoxyquinolin-4-ylamino)-phenyl]-amide;

-   4-(4-Fluoro-phenyl)-2-isopropyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-ylamino)-phenyl]-amide;

-   1-ethyl-3-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-ylsulfanyl)-phenyl]-amide;

-   3-(4-Fluoro-phenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-ylsulfanyl)-phenyl]-amide;

-   3-(4-Fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic    acid {4-[(6,7-dimethoxy-quinolin-4-yl)-methyl-amino]-phenyl}-amide;

-   1-Ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic    acid {4-[(6,7-dimethoxy-quinolin-4-yl)-methylamino]-phenyl}-amide;

-   3-(4-Fluoro-phenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic    acid [4-(6,7-dimethoxy-quinazolin-4-yloxy)-phenyl]-amide;

-   1-Ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic    acid [4-(6,7-dimethoxy-quinazolin-4-yloxy)-phenyl]-amide;

-   1-Ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-2-methoxyphenyl]-amide;

-   1-Methyl-3-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-2-methoxy-phenyl]-amide;

-   1-Isopropyl-3-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-2-methoxy-phenyl]-amide;

-   1-Methyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-2,3-difluoro-phenyl]-amide;

-   1-Ethyl-3-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-2,3-difluoro-phenyl]-amide;

-   1-Ethyl-3-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-methyl-phenyl]-amide;

-   3-(4-Fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-methyl-phenyl]-amide;

-   3-(4-Fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-methoxy-phenyl]-amide;

-   1-Ethyl-3-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-methoxy-phenyl]-amide;

-   1-Ethyl-3-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic    acid    [3-chloro-4-(6,7-dimethoxy-quinolin-4-yloxy)-3-methoxy-phenyl]-amide;

-   1-Ethyl-3-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic    acid    [4-(6,7-dimethoxy-quinolin-4-yloxy)-2-dimethylamino-phenyl]-amide;

-   3-(4-Fluoro-phenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic    acid    [4-(6,7-dimethoxy-quinolin-4-yloxy)-2-dimethylamino-phenyl]-amide;

-   1-Ethyl-3-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-isopropyl-phenyl]-amide;

-   3-(4-Fluoro-phenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-isopropyl-phenyl]-amide;

-   1-Ethyl-3-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-2,3-dimethyl-phenyl]-amide;

-   3-(4-Fluoro-phenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-2,3-dimethyl-phenyl]-amide;

-   1-Ethyl-3-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic    acid    [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-trifluoromethyl-phenyl]-amide;

-   3-(4-Fluoro-phenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic    acid    [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-trifluoromethyl-phenyl]-amide;

-   1-Ethyl-3-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3,5-dimethyl-phenyl]-amide;

-   3-(4-Fluoro-phenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3,5-dimethyl-phenyl]-amide;

-   3-(4-Fluoro-phenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-methyl-phenyl]-amide;

-   2-Ethyl-4-(4-fluoro-phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic    acid [5-(6,7-dimethoxy-quinolin-4-yloxy)-pyridin-2-yl]-amide;

-   2-Ethyl-4-(4-fluoro-phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-isopropyl-phenyl]-amide;    or

-   4-(4-Fluoro-phenyl)-2-isopropyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic    acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-2-methoxy-phenyl]-amide; or

a pharmaceutically acceptable salt thereof.

19. A method of treating a subject suffering from an AXL- orc-MET-mediated disorder or condition comprising administering to thesubject a therapeutically effective amount of a compound according toany one of preferred Embodiments 1 to 18.20. A method according to preferred Embodiment 19 wherein the AXL- orc-MET-mediated disorder or condition is the development of resistance tocancer therapies.21. A compound according to any one of preferred Embodiments 1 to 18 foruse in the treatment of a subject suffering from an AXL- orc-MET-mediated disorder or condition.22. The method of preferred Embodiment 19 wherein the AXL- orc-MET-mediated disorder or condition is cancer.23. A compound according to preferred Embodiment 21 wherein the AXL- orc-MET-mediated disorder or condition is cancer.24. The method of preferred Embodiment 19 wherein the AXL- orc-MET-mediated disorder is selected from chronic myelogenous leukemia,chronic myeloproliferative disorder, lung cancer, prostate cancer,esophageal cancer, ovarian cancer, pancreatic cancer, gastric cancer,liver cancer, thyroid cancer, renal cell carcinoma, glioblastoma, breastcancer, acute myeloid leukemia, colorectal cancer, uterine cancer,malignant glioma, uveal melanoma, osteosarcoma and soft tissue sarcoma.25. A compound according to preferred Embodiment 21 wherein the AXL- orc-MET-mediated disorder is selected from chronic myelogenous leukemia,chronic myeloproliferative disorder, lung cancer, prostate cancer,esophageal cancer, ovarian cancer, pancreatic cancer, gastric cancer,liver cancer, thyroid cancer, renal cell carcinoma, glioblastoma, breastcancer, acute myeloid leukemia, colorectal cancer, uterine cancer,malignant glioma, uveal melanoma, osteosarcoma and soft tissue sarcoma.26. A method of treating a proliferative disorder in a subject in needthereof, comprising administering to the subject a therapeuticallyeffective amount of a compound according to any one of preferredEmbodiments 1 to 18.27. A compound according to any one of preferred Embodiments 1 to 18 foruse in the treatment of a subject suffering from a proliferativedisorder.28. A method according to preferred Embodiment 26 wherein theproliferative disorder is cancer.29. A compound according to preferred Embodiment 27 wherein theproliferative disorder is cancer.30. A method according to preferred Embodiment 26 wherein theproliferative disorder is selected from chronic myelogenous leukemia,chronic myeloproliferative disorder, lung cancer, prostate cancer,esophageal cancer, ovarian cancer, pancreatic cancer, gastric cancer,liver cancer, thyroid cancer, renal cell carcinoma, glioblastoma, breastcancer, acute myeloid leukemia, colorectal cancer, uterine cancer,malignant glioma, uveal melanoma, osteosarcoma and soft tissue sarcoma.31. A compound according to preferred Embodiment 29 wherein theproliferative disorder is selected from chronic myelogenous leukemia,chronic myeloproliferative disorder, lung cancer, prostate cancer,esophageal cancer, ovarian cancer, pancreatic cancer, gastric cancer,liver cancer, thyroid cancer, renal cell carcinoma, glioblastoma, breastcancer, acute myeloid leukemia, colorectal cancer, uterine cancer,malignant glioma, uveal melanoma, osteosarcoma and soft tissue sarcoma.32. A pharmaceutical composition comprising a compound according to anyone of preferred Embodiments 1 to 18 and a pharmaceutically acceptablecarrier, diluents or excipient therefor.33. A compound of Formula I or a salt thereof,

wherein:

-   -   E is chosen from H, C₁₋₆alkyl optionally substituted by 1-6 R¹⁹,        C₂₋₆alkenyl optionally substituted by 1-6 R¹⁹, C₂₋₆alkynyl        optionally substituted by 1-6 R¹⁹, phenyl optionally substituted        by 1-6 R¹⁹, and C₃₋₆cycloalkyl optionally substituted by 1-6        R¹⁹;    -   G is chosen from H, C₁₋₆alkyl optionally substituted by 1-3 R¹⁹,        C₂₋₆alkenyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkynyl        optionally substituted by 1-3 R¹⁹ phenyl optionally substituted        by 1-3 R¹⁹, C₃₋₆cycloalkyl optionally substituted by 1-3 R¹⁹,        and 3-6 membered heterocyclyl optionally substituted by 1-3 R¹⁹;    -   X is N or C—R₄;    -   Y is N or C-Rid;    -   R₃ is H or C₁₋₆alkyl;    -   D is —O—, —S—, —C(═O)—, —CHOH—, —CH₂—, —NH— or —NC₁₋₆alkyl-;    -   W is CH or N;    -   R_(a), R_(b), R_(e), and R_(d) are independently chosen from H,        C₁₋₆alkyl optionally substituted by 1-6 R¹¹⁹, —CN, and —OR¹¹⁰;        or R_(a) and R_(b) can, together with the atoms linking them,        form a 3-6 membered heterocyclyl optionally substituted by 1-6        R¹¹⁹;    -   R_(1a), R_(1b), R_(1c), and R_(1d) are independently chosen from        H, C₁₋₆alkyl optionally substituted by 1-6 R¹¹⁹, C₃₋₆cycloalkyl        optionally substituted by 1-6 R¹¹⁹, 3-6 membered heterocyclyl        optionally substituted by 1-6 R¹¹⁹, halogen, —CN, —NR¹¹²R¹¹³,        and —OR¹¹⁰;    -   R₄ is chosen from H and C₁₋₆alkyl;    -   R¹⁹ at each occurrence is independently chosen from C₁₋₆alkyl        optionally substituted by 1-6 R³⁹, phenyl optionally substituted        by 1-6 R³⁹, C₃₋₆cycloalkyl optionally substituted by 1-6 R³⁹,        3-6 membered heterocyclyl optionally substituted by 1-6 R³⁹, 5-6        membered heteroaryl optionally substituted by 1-6 R³⁹, halogen,        —CN, —C(═O)OR³⁰, —C(═O)NR³²R³³, —NR³²R³³, —OR³⁰, and ═O;    -   R³⁰, R³² and R³³ at each occurrence is independently chosen from        H, C₁₋₆alkyl, C₁₋₆halolkyl, phenyl, benzyl, C₅₋₆cycloalkyl, 5-6        membered heterocyclyl, and 5-6 membered heteroaryl; or R³² and        R³³ may form, together with the nitrogen atom to which they are        attached, a 5-6 membered heterocyclyl or a 5-6 membered        heteroaryl;    -   R³⁹ at each occurrence is independently chosen from C₁₋₆alkyl,        C₁₋₆haloalkyl, and benzyl;    -   R¹¹⁰, R¹¹², and R¹¹³ at each occurrence is independently chosen        from H and C₁₋₆alkyl optionally substituted by 1-3 R¹²⁹;    -   R¹¹⁹ at each occurrence is independently chosen from C₁₋₆alkyl        optionally substituted by 1-3 R¹⁵⁹, 5-6 membered heterocyclyl        optionally substituted by 1-3 R¹⁵⁹, and halogen;    -   R¹²⁹ and R¹⁵⁹ at each occurrence is independently chosen from        C₁₋₆alkyl, C₁₋₆-haloalkyl, benzyl, and halogen; and    -   n at each occurrence is independently chosen from 0, 1, and 2.        34. A compound according to preferred Embodiment 33, wherein E        is chosen from H, C₁₋₆alkyl optionally substituted by 1-3 R¹⁹,        C₂₋₆alkenyl, C₂₋₆alkynyl optionally substituted by —OH, phenyl        optionally substituted by halogen, and C₃-6cycloalkyl.        34. A compound according to preferred Embodiment 33, wherein E        is chosen from H, C₁₋₆alkyl optionally substituted by 1-3 R¹⁹,        C₂₋₆alkenyl, C₂₋₆alkynyl optionally substituted by —OH, phenyl        optionally substituted by halogen, and cyclohexyl.        35. A compound according to preferred Embodiment 33, wherein E        is chosen from C₁₋₆alkyl optionally substituted by R¹⁹, phenyl,        and p-fluorophenyl.        36. A compound according to preferred Embodiment 33, wherein E        is p-fluorophenyl.        37. A compound according to any of preferred Embodiments 33-36,        wherein G is chosen from H, C₁₋₆alkyl optionally substituted by        1-3 R¹⁹, C₂₋₆alkenyl optionally substituted by 1-3 halogen,        C₂₋₆alkynyl, phenyl optionally substituted by 1-3 halogen,        C₃₋₆cycloalkyl, and 3-6 membered heterocyclyl.        38. A compound according to any of preferred Embodiments 33-36,        wherein G is chosen from H, C₁₋₆alkyl optionally substituted by        1-3 R¹⁹, C₃₋₆alkenyl optionally substituted by 1-3 fluoro,        C₃₋₆alkynyl, phenyl optionally substituted by 1-3 fluoro,        C₃₋₆cycloalkyl, and 6 membered heterocyclyl.        39. A compound according to any of preferred Embodiments 33-36,        wherein G is chosen from H, C₁₋₆alkyl optionally substituted by        R¹⁹, C₃₋₆alkenyl optionally substituted by 2 fluoro,        C₃₋₆alkynyl, phenyl optionally substituted by fluoro,        C₃₋₆cycloalkyl, and tetrahydropyranyl.        40. A compound according to any of preferred Embodiments 33-36,        wherein G is C₁₋₆alkyl optionally substituted by cyclopropyl or        —OH.        41. A compound according to any of preferred Embodiments 33-40,        wherein X is N.        42. A compound according to any of preferred Embodiments 33-40,        wherein X is C—R₄.        43. A compound according to any of preferred Embodiments 33-42,        wherein Y is N.        44. A compound according to any of preferred Embodiments 33-42,        wherein Y is CH.        45. A compound according to any of preferred Embodiments 33-42,        wherein Y is C—R_(1d).        46. A compound according to any of preferred Embodiments 33-45,        wherein R₃ is H.        47. A compound according to any of preferred Embodiments 33-46,        wherein D is —O—, —S—, —C(═O)—, —CHOH—, or —CH₂—.        48. A compound according to any of preferred Embodiments 33-46,        wherein D is —O—, —C(═O)—, —CHOH—, or —CH₂—.        49. A compound according to any of preferred Embodiments 33-46,        wherein D is —O—.        50. A compound according to any of preferred Embodiments 33-49,        wherein W is CH.        51. A compound according to any of preferred Embodiments 33-50,        wherein R_(a), R_(b), R_(c), and R_(d) are independently chosen        from H, C₁₋₆alkyl optionally substituted by 1-6 R¹¹⁹, —CN, and        —OR¹¹⁰; or R_(a) and R_(b) can, together with the atoms linking        them, form a 5-6 membered heterocyclyl.        52. A compound according to any of preferred Embodiments 33-50,        wherein R_(a) is chosen from H, —CN, and —OC₁₋₆alkyl; R_(b) is        chosen from H, C₁₋₆alkyl optionally substituted by 1-6 R¹¹⁹, and        —OR¹¹⁰; R_(c) is chosen from H and —OC₁₋₆alkyl; and R_(d) is        chosen from H and —OC₁₋₆alkyl; or R_(a) and R_(b) can, together        with the atoms linking them, form a 5-6 membered heterocyclyl.        53. A compound according to any of preferred Embodiments 33-50,        wherein R_(a) is chosen from H, —CN, and —OC₁₋₆alkyl; R_(b) is        chosen from H, C₁₋₆alkyl optionally substituted by 6-membered        heterocyclyl, —OH, —OC₁₋₆alkyl, —OCH₂phenyl,        —OC₁₋₆alkyl-O—C₁₋₆alkyl; R_(c) is chosen from H and —OC₁₋₆alkyl;        and R_(d) is chosen from H and —OC₁₋₆alkyl; or R_(a) and R_(b)        can, together with the atoms linking them, form a 5-6 membered        heterocyclyl.        54. A compound according to any of preferred Embodiments 33-50,        wherein R_(a) is chosen from H, —CN, and —OC₁₋₆alkyl; R_(b) is        chosen from H, C₁₋₆alkyl optionally substituted by morpholinyl,        —OH, —OC₁₋₆alkyl, —OCH₂phenyl, —OC₁₋₆alkyl-O—C₁₋₆alkyl; R_(c) is        chosen from H and —OC₁₋₆alkyl; and R_(d) is chosen from H and        —OC₁₋₆alkyl; or R_(a) and R_(b) together form

55. A compound according to any of preferred Embodiments 33-50, whereinR_(a) is chosen from H and —OC₁₋₆alkyl; R_(b) is chosen from H and—OC₁₋₆alkyl; R_(c) is H; and R_(d) is chosen from H and —OC₁₋₆alkyl; orR_(a) and R_(b) together form

56. A compound according to any of preferred Embodiments 33-50, whereinR_(a) is chosen from H and —OC₁₋₆alkyl; R_(b) is chosen from H and—OC₁₋₆alkyl; R_(c) is H; and R_(d) is H; or R_(a) and R_(b) togetherform

57. A compound according to any of preferred Embodiments 33-50, whereinR_(c) and R_(d) are H, and R_(a) and R_(b) are —OC₁₋₆alkyl; or R_(a) andR_(b) together form

58. A compound according to any of preferred Embodiments 33-50, whereinR_(a) is —OC₁₋₆alkyl; R_(b) is —OC₁₋₆alkyl; R_(c) is H; and R_(d) is H.59. A compound according to any of preferred Embodiments 33-40 or 42-58,wherein R⁴ is H.60. A compound according to any of preferred Embodiments 33-59, whereinR_(1a), R_(1b), R_(1c), and R_(1d) are independently chosen from H,C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl, halogen, —NH₂, —NHC₁₋₆alkyl₂,—N(C₁₋₆alkyl)₂, —OH, and —OC₁₋₆alkyl.61. A compound according to any of preferred Embodiments 33-59, whereinR_(1a), R_(1b), R_(1c), and R_(1d) are independently chosen from H,C₁₋₃alkyl, C₁₋₃haloalkyl, cyclopropyl, halogen, and —OC₁₋₃alkyl.62. A compound according to any of preferred Embodiments 33-59, whereinR_(1a), R_(1b), R_(1c), and R_(1d) are independently chosen from H,halogen, and —OC₁₋₃alkyl.63. A compound according to any of preferred Embodiments 33-59, whereinR_(1a), R_(1b), R_(1c), and R_(1d) are independently chosen from H andhalogen.64. A compound according to any of preferred Embodiments 33-59, whereinR_(1a), R_(1c), and R_(1d) are H and R_(1b) is chosen from H, C₁₋₃alkyl,C₁₋₃haloalkyl, cyclopropyl, halogen, and —OC₁₋₃alkyl.65. A compound according to any of preferred Embodiments 33-59, whereinR_(1a), R_(1c), and R_(1d) are H and R_(1b) is chosen from H, halogen,and —OC₁₋₃alkyl.66. A compound according to any of preferred Embodiments 33-59, whereinR_(1a), R_(1c), and R_(1d) are H and R_(1b) is fluoro.67. A compound according to any of preferred Embodiments 33-66, whereinR¹⁹ at each occurrence is independently chosen from C₁₋₆alkyl, phenyloptionally substituted by 1-3 halogen, C₃₋₆cycloalkyl, 5-6 memberedheterocyclyl, 5-6 membered heteroaryl optionally substituted by 1-3C₁₋₆alkyl, halogen, —CN, —C(═O)OH, —C(═O)OC₁₋₆alkyl,—C(═O)N(C₁₋₆alkyl)₂, —C(═O)pyrrolidinyl, —C(═O)morpholinyl,—N(C₁₋₆alkyl)₂, —OH, —OC₁₋₆alkyl, —Obenzyl, and ═O.68. A compound according to any of preferred Embodiments 33-67, whereinR³⁰, R³² and R³³ at each occurrence is independently chosen from H andC₁₋₆alkyl.69. A compound according to any of preferred Embodiments 33-68, whereinR³⁹ at each occurrence is C₁₋₆alkyl.70. A compound according to any of preferred Embodiments 33-69, whereinR¹¹⁰, R¹¹², and R¹¹³ at each occurrence is independently chosen from Hand C₁₋₆alkyl.71. A compound according to any of preferred Embodiments 33-70, whereinR¹¹⁹ at each occurrence is independently chosen from 6 memberedheterocyclyl and halogen.72. A compound according to any of preferred Embodiments 33-70, whereinR¹¹⁹ at each occurrence is independently chosen from morpholinyl andfluoro.73. A compound according to any of preferred Embodiments 33-72, whereinR¹²⁹ and R¹⁵⁹ at each occurrence is independently chosen from C₁₋₆alkyland halogen.74. A compound according to any of preferred Embodiments 33-73, whereinn at each occurrence is 2.75. A compound according to preferred Embodiment 33, wherein E isp-fluorophenyl; G is C₁₋₄alkyl optionally substituted by cyclopropyl,—OH, or —OC₁₋₃alkyl; X, Y, and W are CH; R₃, R_(c), R_(d), R_(1b) andR_(1c) are H; D is —O—; R_(a) and R_(b) are —OCH₃ or together form

and R_(1a) is fluoro.

1-21. (canceled)
 22. A method of inhibiting AXL, c-met, or AXL and c-met, comprising contacting a cell with an effective amount of a compound which is 3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide having the structure

or a pharmaceutically acceptable salt thereof.
 23. A method according to claim 22, wherein AXL is inhibited.
 24. A method according to claim 22, wherein c-met is inhibited.
 25. A method according to claim 22, wherein AXL and c-met are inhibited.
 26. A method of treating an AXL or c-met-mediated disorder or condition in a subject, comprising administering to said subject a therapeutically effective amount of a compound which is 3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide having the structure

or a pharmaceutically acceptable salt thereof.
 27. A method according to claim 26, wherein said therapeutically effective amount of 3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide, or a pharmaceutically acceptable salt thereof, is from about 0.001 mg/kg to about 100 mg/kg.
 28. A method according to claim 26, wherein said therapeutically effective amount of 3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide, or a pharmaceutically acceptable salt thereof, is from about 0.1 mg/kg to about 10 mg/kg.
 29. A method according to claim 26, wherein said therapeutically effective amount of 3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide, or a pharmaceutically acceptable salt thereof, is from about 0.5 mg/kg to about 5 mg/kg.
 30. A method according to claim 26, wherein said therapeutically effective amount of 3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide, or a pharmaceutically acceptable salt thereof, is from about 1 mg/kg to about 2 mg/kg.
 31. A method according to claim 26, wherein said 3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide, or a pharmaceutically acceptable salt thereof, is administered to said subject daily.
 32. A method according to claim 26, wherein said disorder or condition is chronic myeloproliferative disorder.
 33. A method according to claim 26, wherein said disorder or condition is cancer.
 34. A method according to claim 33, wherein said cancer is resistant to at least one cancer therapy.
 35. A method according to claim 33, wherein said cancer is selected from chronic myelogenous leukemia, lung cancer, non-small cell lung cancer, prostate cancer, esophageal cancer, ovarian cancer, pancreatic cancer, gastric cancer, liver cancer, thyroid cancer, renal cell carcinoma, glioblastoma, breast cancer, acute myeloid leukemia, colorectal cancer, uterine cancer, malignant glioma, melanoma, uveal melanoma, osteosarcoma, and soft tissue sarcoma.
 36. A method according to claim 35, wherein said cancer is selected from non-small cell lung cancer, breast cancer, pancreatic cancer, colorectal cancer, melanoma, and glioblastoma.
 37. A method according to claim 36, wherein said cancer is non-small cell lung cancer.
 38. A method according to claim 36, wherein said cancer is breast cancer.
 39. A method according to claim 36, wherein said cancer is pancreatic cancer.
 40. A method according to claim 36, wherein said cancer is colorectal cancer.
 41. A method according to claim 36, wherein said cancer is melanoma.
 42. A method according to claim 36, wherein said cancer is glioblastoma.
 43. A pharmaceutical composition, comprising a therapeutically effective amount of a compound which is 3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide having the structure

or a pharmaceutically acceptable salt thereof, and another therapeutic agent. 